Hepatic Circulation and Toxicology: Drug Metabolism Reviews February 1997

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Hepatic Circulation and Toxicology
Article in Drug Metabolism Reviews · February 1997

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DRUG METABOLISM REVIEWS, 29(1&2), 369-395 (1997)
Drug Metabolism Reviews Downloaded from informahealthcare.com by Francis A Countway Library of Medicine on 05/30/14
HEPATIC CIRCULATION AND

TOXICOLOGY *
W. WAYNE LAUTTt
Department of Pharmacology and Therapeutics
Faculty of Medicine
University of Manitoba
Winnipeg, Manitoba, Canada, R3E OW3
M. PAULA MACEDO
Institute of health Sciences
Quinta da Granja-Trav. da Granja
For personal use only.
Monte da Caparica 2825, Portugal
I. NORMAL PHYSIOLOGY ............................................. 370

A Overview ............................................................... 370
B. Portal Vein .................................... ........................ 371
C. Hepatic Artery ........................................................ 373
D. Hepatic Circulation and Oxygen Supply ........................ 375
E. Sinusoidal Perfusion ................................................. 377
11. TOXICOLOGY AND HEPATIC CIRCULATION ............... 378
A. Hepatic Blood Flow ................................................. 378
B. Veno-occlusive Toxins .............................................. 380
C. Heterogeneity of Perfusion.. ....................................... 38 1
D. Capillarization ........................................................ 383
E. Ethanol ................................................................. 384
F. Methodological Considerations ................. ................,.. 385
*Contributed in honor of Gabriel L. Plaa, Ph.D.

+To whom correspondence should be addressed.
369
Copyright 0 1997 by Marcel Dekker, Inc.

370 LAUTT AND MACEDO
111. FREE RADICALS AND ANTIOXIDANTS ....................... 387

Acknowledgments......................................................... 389
References .................................................................. 390
I. NORMAL PHYSIOLOGY
A. Overview
The liver is the largest internal organ in the body, weighing about 1.5
kg in an adult, and receiving about 1 mL of blood/g of tissue. The liver
has 25% of the cardiac output flowing through it, being processed by it,
and influencing its functions. The circulation of the liver is unique ana-
tomically, functionally, and in the mechanisms that regulate it.
The liver is interposed between the enteric circulation, the site of ab-
sorption of most xenobiotics, and the systemic circulation. The biological

roles of the liver are complex, diverse, and numerous, often interdepen-
dent and regulated by redundant control systems. Combined with the
unique ability of the liver to regenerate, toxic effects on the liver must
be quite severe in order for there to be significant clinical consequences.
Nevertheless, a variety of homeostatic disturbances seen with diseased liv-
ers result, usually in unknown manners, from disturbance of hepatic ho-
meostatic roles.
Two-thirds of the blood supply to the liver has already passed through
the organs that drain into the portal vein. The metabolic activities of the
stomach, spleen, pancreas, omentum, and large and small intestines are
highly variable depending upon the prandial state. The liver cannot con-
trol the portal blood flow, which is simply the sum of the outflow of all
of these organs. The remaining blood flow to the liver is through the
hepatic artery. Considering the metabolic importance of the liver, it is
interesting that the hepatic artery appears to be the only artery in the body
that is not regulated by the parenchymal metabolism of the supplied tis-
sue. The hepatic artery responds to changes in portal blood flow and
adjusts its flow in the opposite direction in order to minimize or buffer
changes in total hepatic blood flow that would otherwise occur. The oxy-
gen, nutrient, and hormonal content of the portal blood may vary consid-
erably with daily activity. Changes in portal flow will lead to altered ra-
tios of portal and hepatic arterial flow with consequent impact on oxygen
supply to the liver.
HEPATIC CIRCULATION AND TOXICOLOGY 37 1
The two input vessels supply mixed blood to hepatic sinusoids. which
are the equivalent to the capillaries in other tissues. The sinusoids have a
number of features peculiar to the liver including their relative density
compared to the parenchymal cells which, on average, are in contact with

a sinusoid on two sides of the cell. Because of the unique microvascular
anatomy of the liver. very strong gradients exist between the inflow and
outflow sides of the hepatic circulation. Dramatic gradients exist for any
compound that is efficiently extracted or metabolized on passage through
the liver or added to the sinusoidal blood. Thus, the microenvironment
surrounding each parenchymal cell is quite distinct as the cells progress
from the inlet to the outlet side of the liver. This distinctness in the mi-
croenvironment also leads to distinctness in metabolic processing and sus-
ceptibility to toxic compounds. Because of the increasing awareness of the
role of free radicals in toxicology and the importance of oxygen levels in
radical formation, blood flow and oxygen supply become of considerable
consequence to toxicology. In the following sections we review the basic
regulatory processes and characteristics of the hepatic circulation, and at-
tempt to relate the basic physiology with toxicology. More detailed spe-
cific references for the fundamentals of the hepatic circulation can be
obtained from recent reviews [ 1-31.
B. Portal Vein
About 20% of the cardiac output passes through the extrahepatic splan-
chnic organs. Chemicals are absorbed from the gastrointestinal tract into
the portal blood, and a variety of hormones and vasoactive compounds are
secreted into the portal blood as part of the response to feeding. The portal
venous blood is, therefore, unique in its chemical composition. The por-
tal vein collects the blood from the various organs and delivers it to the
liver under an extremely low driving blood pressure of 7-10 mm Hg. For
technical reasons it is often difficult even to be able to detect a signifi-
cant pressure gradient across the liver, between the portal vein and the
inferior vena cava. This gradient is normally no more than 1-2 mm Hg
pressure. One of the buffer roles of the liver is achieved through what is
known as the hepaficprsf-passclearance. Many of the hormones that enter
the portal blood are significantly extracted by the liver in the first passage.
Bioavailability of many drugs and toxins is severely restricted by the ability
of the liver to extract these compounds from blood. It is for this reason
that certain types of drugs may be more effectively administered by sub-
lingual or transdermal routes to avoid absorption into the portal vein and
to escape the hepatic first-pass effect. Highly lipid-soluble drugs avoid this
effect by virtue of their absorption into intestinal lymphatic vessels which,
in turn, drain directly into the central venous compartment and therefore
bypass the liver.

Venous resistance within the liver is extremely low and appears to be
primarily focused at specific presinusoidal and postsinusoidal venous lo-
cations. The total and relative resistance at the sites changes dramatically
with physiological and pathological stimuli, and becomes dramatically mod-
ified in cirrhosis. The nonpathological vascular resistance does not alter
portal blood flow through the liver but does affect portal and intrahepatic
blood pressures. Because the liver and portal venous tributaries are ex-
tremely compliant, an increase in hepatic venous outflow resistance suffi-
cient to elevate intrahepatic pressure by less than 10 mm Hg will lead to
a doubling of hepatic and splanchnic blood volumes [4], with a resultant
severe decrease in venous return and cardiac output and a rapid cardio-
vascular collapse. This is most dramatically seen in the canine response
to anaphylactic shock, which results in a unique hepatic venous constric-
tion with the animal responding as if it had been subjected to a massive

hemorrhage because of the splanchnic pooling of blood. Hepatic venous
resistance vessels are strongly affected by a number of toxicants described
later.
The pre- and postsinusoidal resistance sites are passively distensible and
largely account for the observation that portal flow can double with por-
tal pressure increasing by no more than 2 mm Hg [ 5 ] . The relationship
between the distending blood pressure and the passively distensible pre-
and postsinusoidal resistance sites has been mathematically described us-
ing the index of contractility, which is the product of vascular resistance
and distending pressure cubed, with the distending pressure defined as the
average of the pressure on either side of the resistance site [6]. These pres-
sures can be adequately estimated by the use of catheters advanced beyond
the hepatic venous resistance sites and measuring pressure in a nonwedged
capacity. This methodology has been described and evaluated in the cat
[7] and dog [8] under a variety of physiological conditions [9,10] and has
been compared with the more classical balloon occlusion technique which
can be shown to be unable to distinguish between the pre- and postsin-
usoidal resistance [ll]. The use of the venous catheter technique provides
what we have referred to as lobar venous pressure, which is similar to
the pressure of the hepatic sinusoidal bed. The gradient between the lo-
bar pressure and extrahepatic central venous pressure represents post-
sinusoidal resistance whereas the gradient between portal venous pressure
and the lobar venous pressure represents the resistance of the blood ves-
sels between these two catheters, which includes the portal venous
HEPATIC CIRCULATION AND TOXICOLOGY 373
branches, hepatic sinusoids, and small hepatic venules. For reasons de-
scribed elsewhere [lo], we believe the gradient between the portal vein and
the lobar venous catheter to represent primarily presinusoidal portal venous
resistance.
Drugs delivered to the liver are able to affect both resistance sites. A
wide range of doses of norepinephrine produce approximately equal con-
striction at the pre- and postsinusoidal site. Hepatic sympathetic nerves
activate these sites, but in a differential manner, with 2 Hz nerve stimu-
lation resulting almost exclusively in a hepatic venous resistance response
with presinusoidal constriction becoming significant at 4 Hz. The hepatic
venous response is maximal at 4 Hz but the presinusoidal response con-
tinues to rise to account for approximately 40% of the total resistance
change at 10 Hz [lo]. Use of the new index of contractility allows de-
termination of whether the vascular resistance changes are active or pas-
sive. The passive changes in the distensible resistance vessels are in the
same range as those able to be elicited by maximal active stimulation [6].
The index of contractility calculation yields a value that does not change
with passive changes, in contrast to the changes in resistance or pressure

gradients, which are dependent upon both active and passive responses.
This is an important distinction when testing for the mechanism of action
of vasoactive compounds used to treat portal hypertension.
C. Hepatic Artery
Hepatic arterial blood flow is affected by circulating vasoactive com-

pounds, sympathetic nerves, and by intrinsic regulatory mechanisms. The
intrinsic regulatory mechanisms are very powerful and interact with all
other factors in what may be complex and unexpected ways. The hepatic
artery may provide most, or all, of the oxygen requirements to the liver.
Because of the importance of oxygen tension to free-radical formation and
detoxification, a firm understanding of hepatic arterial regulation is cru-
cial.
An unusual feature about the hepatic artery is that it is not regulated
according to the metabolic demands or oxygen supply of the liver. This
was first clearly demonstrated in 1977 [12,13], where isovolemic hemo-
dilution led to a decrease in hepatic oxygen delivery, with a reduction in
portal venous and hepatic venous oxygen content and PO, and elevated
pCO,, without consequence to the vascular tone of the hepatic artery. This
observation was followed by other studies that demonstrated that stimula-
tion or inhibition of enzyme activity and oxygen consumption were with-
out effect on the hepatic artery, which was still capable of responding to
appropriate dilator stimuli [14]. A variety of studies have since supported

this conclusion. These early studies led to the observation that the primary
factor regulating hepatic blood flow was what we have termed the hepatic
arterial bufSer response (HABR), which is the inverse response of hepatic

arterial conductance to changes in portal blood flow. For example, when
portal flow increases, hepatic arterial flow decreases rapidly, tending to
minimize the impact of portal flow changes on total hepatic blood flow.
The mechanism of the HABR operates in a manner consistent with the
following hypothesis. The hepatic acinus, described later, represents a clus-
ter of parenchymal cells arranged like a 2-mm berry on a vascular stalk,
the portal triad, which leads into the center of each acinus. The terminal
branches of the hepatic arteriole, portal venule, and bile ductule lie within
an enclosed space surrounded by a limiting plate of cells. The fluid bathing
these vessels and contained with the limiting plate comprises the space of
Mall. Adenosine is proposed to be continuosly secreted into the space of
Mall (independent of general parenchymal cell oxygen supply or demand)
and the local concentration of adenosine determines the tone of the hepatic
artery. Adenosine can be washed away into the bloodstream of the portal
vein or hepatic artery, and the concentration in the space of Mall is pro-
posed to be regulated by this washout.
The HABR is accounted for by this mechanism whereby a reduced
portal blood flow washes away less adenosine and the accumulated adenos-
ine leads to dilation of the hepatic artery. Dipyridamole. an adenosine up-
take antagonist, potentiated the response to exogenous adenosine and to the
HABR [15]. The HABR can be competitively antagonized by adenosine
receptor blockers that can lead to a complete elimination of the HABR,
thus suggesting that no other mechanism is required to account for this
response [ 161.
In attempting to determine the mechanism of the HABR, we have con-
sidered a variety of alternate hypotheses which are discussed elsewhere
[ 171. In consideration of possible vasodilator substances that could account
for the mechanism, we initially did not consider adenosine to be a likely
mediator because it was generally accepted that adenosine was produced
by breakdown of adenine nucleotides and was directly tied to the energy
status of the cell, and served as a link between metabolic activity and
vascular regulation. The adenosine-mediated HABR is not altered by
changes in oxygen supply or demand in the liver, thus leading us to con-
clude that adenosine is produced at a constant rate and secreted into the
space of Mall with the concentration being dependent upon the rate of
washout. Adenosine production has been shown to be produced in the heart
in an oxygen-independent manner by demethylation of S-adenosylhomo-
cysteine [181. S-Adenosylmethionine is the immediate precursor of S-adeno-
sylhomocysteine; the former compound is available in the liver in very

high concentration and serves a number of functions. It seems most likely
that this is the pathway of adenosine production involved with regulation
of the hepatic artery. The effect of manipulations of hepatic S-adenosyl-

methionine content on the HABR has not been evaluated. Whether S-
adenosylmethionine regulation and levels in the hepatic parenchymal cells
are related to that seen in the cells that secrete adenosine into the space
of Mall is unclear.
The HABR occurs in recently transplanted livers and has been suggested
as a valuable index of integrity of the vascular reconnections. A brief
occlusion of the portal inflow should yield a brisk dilation of the hepatic
artery [19]. Similarly, the HABR occurs in diseased livers and has also
been suggested to be the best prognostic indicator of the outcome of sur-
gery using portacaval shunts to reduce the pressure in portal hypertension
[20]. Very severe cirrhotics may not show an HABR but this has not been
well studied [21].
The second form of intrinsic regulation in the hepatic artery is auto-
regulation, which is the intrinsic ability of a blood vessel to minimize

changes in flow secondary to changes in perfusion pressure. Although
previously believed to be mediated by a myogenic mechanism, the auto-
regulatory mechanism in the hepatic artery is through the same mechanism
as that controlling the HABR [22]. In this situation, if arterial pressure
decreases, hepatic arterial flow decreases and thus washes away less ad-
enosine from the space of Mall with the accumulated adenosine resulting
in hepatic arterial dilation. Thus, it is proposed that autoregulation and the
HABR operate via the same mechanism. Both forms of intrinsic HA regu-
lation are shown to be antagonized by administration of the adenosine
receptor antagonist, 8-phenyltheophylline, in a dose-dependent manner in
parallel with antagonism of the vasodilator effect of exogenous adenosine.
Although we have recently demonstrated that a similar flow-dependent
adenosine-based mechanism of autoregulation in the intestine is antagonized
by nitric oxide [23], a similar involvement of nitric oxide is not seen in
the liver (Macedo and Lautt, unpublished observations).
D. Hepatic Circulation and Oxygen Supply
The hepatic arterial buffer response is a sufficiently powerful response

to regulate the tone of the hepatic artery from fully dilated, when portal
flow is severely reduced, to fully constricted, when portal flow is doubled
[24]. The oxygen delivery through the hepatic artery can thus be dramati-
cally altered secondary to changes in portal blood flow. Although the
hepatic artery is not directly controlled by hepatic oxygen supply or de-

mand, the effect of the buffer response can preserve oxygen supply in
situations of reduced cardiac output, including the response to hemorrhage.
During hemorrhage, generalized arterial constriction occurs with the no-

table exception being the hepatic artery which undergoes dilation. This
protective dilation can be prevented by preventing the decrease in portal
blood flow or by blocking adenosine receptors [25].
Attempts to increase oxygen delivery to the liver by administration of
vasodilators must be approached with caution. It has been frequently re-
ported in the literature that vasodilators or vasoconstrictors affect all ar-
teries similarly with the exception of the hepatic artery, which is often
noted to change in the opposite direction. We have demonstrated that
systemically administered vasodilators such as glucagon, isoproterenol, and
adenosine, all of which produce direct dilation of the hepatic artery, can
actually lead to a decrease in hepatic arterial flow secondary to the increase
in blood flow to the extrahepatic splanchnic organs, with a consequent
increase in portal flow and activation of the buffer response 1261. Even
when the buffer response is successfully activated to lead to an increased

arterial flow, the consequence on net oxygen delivery is not easily pre-
dicted. The oxygen content in portal venous blood may be quite variable
and, considering that the hepatic arterial buffer response does not com-
pletely compensate for the change in portal flow, the net effect on oxy-
gen delivery will depend upon the relative oxygen content of the portal
vein and hepatic artery, and on the buffer capacity.
Attempts to selectively manipulate hepatic arterial flow through devel-
opment of stimulators of the metabolic pathway that produces adenosine
involved with regulation of the buffer response, or with the use of selec-
tive adenosine uptake antagonists, may prove beneficial.
Attempts to manipulate the other endogenous vasodilator regulator of
hepatic circulation, nitric oxide, are less likely to be productive. The role
of nitric oxide in hepatic circulatory regulation is very organ specific and
shows dramatic contrasts with other gastrointestinal vascular beds, including
the small intestine. For example, inhibition of nitric oxide production by
the nitric oxide synthase antagonist L-NAME causes increased basal tone
in the circulation of the small intestine, accompanied by potentiation of
autoregulation, potentiation of the vasodilator effects of adenosine and
isoproterenol, and potentiation of nerve-induced vasoconstriction (second-
ary to blockade of nitric oxide induced, shear stress-dependent inhibition
of norepinephrine release) [23,27,28], In contrast, nitric oxide synthase
antagonism does not modify basal tone in the hepatic artery or portal vein,
nor does it lead to potentiation of autoregulation or the action of other
vasodilators (Macedo and Lautt, unpublished observations). Nitric oxide
does produce increased shear stress at the site of vasoconstriction, lead-

ing to nitric oxide release from the endothelial cells which causes post-
junctional inhibition of vasoconstrictors (Macedo and Lautt, unpublished
observations). The use of suppressors of other endogenous affectors of

hepatic circulation is not sufficiently well delineated to allow prediction of
effectiveness of pharmaceutical intervention.
E. Sinusoidal Perfusion
The portal vein and hepatic artery subdivide within the liver, and the
terminal branches of each vessel travel in intimate contact within the space
of Mall to the center of each of the 100,OOO hepatic functional units, the
acini. The hepatic acinus is a cluster of parenchymal cells about 2 mm
in diameter that is supplied with portal and arterial blood that enters into
the central zone (Rappaport’s zone 1) where the blood is well mixed [29].
Blood flows outward to the periphery of the acinus, with concurrent flow
in adjacent sinusoids. All exit points from terminal hepatic venules are at
the periphery (zone 3) of the acinus and diffusion from zone 3 to zone 1
is not possible. This vascular arrangement allows the activity of the pa-
renchymal cells to develop strong gradients from zone l to 3, including
the ability to extract selected compounds with virtually 100% efficency.
Blood passing the full length of a sinusoid (220-480 pm) is sequentially
distributed to approximately 20 hepatocytes [30]. There is substantial evi-
dence that the microvascular environment of the hepatocyte regulates hepa-
tocyte function. Heterogeneity of hepatic enzyme distribution across the
acinus has been reviewed [3 1-35].
The hepatocytes are arranged in a syncytium of plates, a single cell in
thickness. The rich sinusoidal network forms a multiple interconnecting
lacunae that floods the plates of parenchymal cells on both sides. The
sinusoidal endothelial cells were previously believed to contain large pores
that offered no resistance to passage of any plasma constituents. It has
become clear that these large pores were artifacts of preparation and it now
appears that the sinusoidal cells contain fenestrae of 100-300 A diameter
[36]. The fenestrae are capable of sieving albumin [36]. Thus contact with
parenchymal cells is highly likely to be altered, for any compounds bound
to albumin and lipoprotein, by changes in fenestrae diameter. Morphologi-
cal studies suggest that the fenestrations are reduced in size by norepineph-
rine and serotonin [37], increased by elevated venous pressure [36,38],
increased by acute alcohol exposure, and decreased by chronic alcohol
exposure [39].
11. TOXICOLOGY AND HEPATIC CIRCULATION

A. Hepatic Blood Flow
Hepatic clearance of many drugs is blood flow dependent. Although not

completely consistent, generally compounds with high hepatic extraction
show clearance rates that are directly dependent upon hepatic blood flow.
If less compound is delivered to the liver, less compound is removed from
the circulation. In contrast, generally, compounds with lower extraction
ratios tend to be blood flow independent. This area has been reviewed
[1,40]. Clearance of many endogenous compounds has not been well stud-
ied relative to hepatic blood flow, but clearance of a number of impor-
tant hormones, including aldosterone and corticosterone [41], is blood flow
dependent. We have proposed that one of the major roles of the HABR
tending to maintain total hepatic blood flow constant is that this mecha-
nism also tends to maintain hepatic clearance of important endogenous
compounds constant. Normally, when considering endocrine regulation, one
focuses on the rate of production and entry of the hormone into the blood-
stream. Of equal importance, in order for the endocrine gland to afford

fine control of hormone levels, a relatively constant background clearance
rate of the hormone from blood must be maintained. If a hormone level
is to be rapidly adjustable by altered output from the endocrine gland,
rapid turnover of the hormone must occur. It is important that the high
catabolic rate be maintained as constant as possible in order that the hor-
mone levels can be accurately controlled by the glandular output. If he-
patic blood flow was not prevented from rapid, transient changes secondary
to similar changes in the portal venous flow, endocrine homeostasis would
be imperiled. Thus, any toxic reaction that leads to impaired HABR would
be anticipated to result in subtle endocrine and metabolic disturbances.
Chronic alterations in hepatic blood flow occur with the normal aging
process. Clearance of a large number of drugs declines with age. The
decline does not appear to be attributable to reduced activity of drug-
metabolizing enzymes, with the possible exception of a few highly spe-
cific cytochrome P450 forms. Hepatic blood flow declines significantly with
aging and is suggested to account for the predominance of reduced hepatic
drug clearance in the elderly [42,43]. Although high-clearance drugs may
require lower dosage in the elderly, the relationship to toxic effects of
drugs has not been adequately evaluated.
Similarly, clearance of drugs with a marked first-pass effect is decreased
in the presence of a portacaval shunt. Because the bioavailability of many
compounds, including beta adrenergic antagonists, calcium channel
blockers, and several analgesics and anxiolytics, will be increased in pa-
tients with a surgical portacaval shunt or endogenous portal systemic

shunts, such as seen in cirrhosis, doses of such compounds are recom-
mended to be adjusted downward to avoid toxicity [44,45]. Creation of a
portacaval shunt leads to hepatic atrophy and reduced levels of cytochrome

P450. A number of liver enzymes are not affected; the activities of four
mixed-function oxidases are reduced and the heme oxygenase rate-limit-
ing enzyme in catabolism of heme to bilirubin is enhanced [46]. Consid-
erable differences in drug metabolism and possibly toxicity would be an-
ticipated in patients with portacaval shunts or reduced hepatic flow due to
age.
The toxic effect of drugs on the liver has often been linked to distur-
bance of blood flow. The phenothiozine derivatives, thioridizine and chlor-
promazine, increase hepatic vascular resistance in cats, rats, and dogs,
leading to elevations in portal pressure and decreases in cardiac output and
portal flow [47]. A single clinically relevant dose of the immunosuppres-
sant cyclosporine led to a greater decrease in total hepatic blood flow than
what is seen for renal blood flow, where the renal vasoconstriction has
been attributed with at least partially accounting for nephrotoxicity. The

potential impact on hepatic function has not been fully evaluated [48].
There has evolved a consensus that much of the postsurgical hepatic
complications seen in patients is related to hepatic circulatory disruption
caused by the anesthetics. Gelman [49] reviewed the area of general an-
esthesia and hepatic circulation. He concluded that the majority of anes-
thetics decrease portal blood flow in association with a decrease in car-
diac output, but that hepatic arterial blood flow can be preserved,
decreased, or increased. Hepatic oxygen deprivation is believed to be a
significant factor in the production of hepatotoxic reactions to anesthetics.
Although it has been suggested that anesthetic agents be ranked by their
ability to preserve hepatic blood flow in relation to hepatic oxygen con-
sumption, no detailed formalized ranking appears to exist although vari-
ous anesthetics are extensively reviewed by Gelman [49]. Halothane ap-
pears to be the most hepatotoxic compound and the toxicity may relate to
the dramatic hepatic circulatory disruptions seen, with decreases occurring
in both portal and hepatic arterial flow. and a reduced hepatic arterial
autoregulation and hepatic arterial buffer response [50-521.
Toxicant interactions with blood flow may be related primarily to the
oxygen delivery and alterations in free-radical formation that are oxygen
dependent (discussed later). The role of circulatory dysfunction within the
liver for potentiation of hepatotoxic effects can be assumed from studies
demonstrating the importance of oxygen supply to toxicity. Shingu et a1
[53] demonstrated that rats pretreated with phenobarbital showed potenti-
ated hepatic injury in response to a variety of anesthetics including halo-
thane, enflurane, isoflurane, thiopental, and fentanyl when administered

10% oxygen. No agent given with 20% or 100% oxygen demonstrated
hepatotoxicity. Liver temperature was also demonstrated to be important
in determining hepatotoxicity with mild hypothermia (32"-34"C) preventing

hepatotoxicity by enflurane and isoflurane but not by halothane when ad-
ministered with 10% oxygen [53]. Although the HABR is seen in cirrhotic
livers, the buffer capacity may be insufficient to maintain a normal oxy-
gen supply [54] and there is suggestion that severely diseased livers lose
the HABR [26].
Ischemia or hypoxia may lead to temporary protection in some in-
stances. Cellular acidosis, a consequence of ischemia or hypoxia, is pro-
tective against death of hepatocytes from a variety of toxicants, including
oxidant chemicals, ionophores, and mitochondrial inhibitors [%I. During
injury, hydrolytic enzymes with neutral or alkaline pH are activated. Their
activities are strongly inhibited by acidotic pH, but reperfusion, which
causes a rise of intracellular pH, releases this inhibition leading to reper-
fusion injury [56]. Chagoya de Sanchez's group has demonstrated that
adenosine, which is produced by an ischemic or hypoxic liver, is an ef-

fective hepatoprotector against the liver damage induced by CCl,, ethanol,
and cyclohexamide [57,58]. These agents cause an increase in oxidant
stress. In the presence of adenosine, free-radical-induced damage was
decreased but it is suggested that the protective effect is not directly due
to adenosine but rather to free-radical scavenging catabolic products of
adenosine, such as uric acid [59]. It is unlikely that adenosine's protec-
tive effect is mediated by an increase in hepatic blood flow since adenos-
ine produced by hepatic parenchymal cells is downstream from the arte-
rial resistance vessels and will not, therefore, have access to the resistance
vessels. This is consistent with the anatomy of the acinus and the obser-
vation that reduced PO, in hepatic arterial perfusate leads to the hepatic
release of adenosine without producing significant arterial vasodilation
( b u t t and Legare, unpublished observations).
B. Veno-occlusive Toxins
A number of toxins, seen in plants consumed as herbal remedies or teas

or that appear as contaminants in foods, produce severe occlusion of the
hepatic veins leading to hemorrhagic necrosis mainly restricted to zone 3
of the acinus. Serious outbreaks of veno-occlusive disease have been re-
ported in Jamaica and India where contamination occurred from seeds of
plants of the Senecio species contaminating commercial grain stocks [60].
It has been suggested that compounds such as azathioprine, monocrotaline,
and dacarbazine produce hepatic veno-occlusive disease primarily as a

result of injury to the endothelial cells subsequent to a profound depletion
of glutathione. Supplemental glutathione protects against these toxicants.
It is possible that glutathione exported from hepatocytes may serve a pro-

tective function for endothelial cells that would be exposed to the glu-
tathione concentration in the space of Disse before the glutathione is di-
luted in the sinusoidal circulation. Thus, a condition of reduced glutathione
concentration in hepatocytes might be anticipated to potentiate toxicity of
compounds that act primarily on endothelial cells [61].
C. Heterogeneity of Perfusion
Heterogeneity of blood flow occurs at different levels within the liver.

The most obvious heterogeneity occurs at the smallest vascular unit, the
sinusoid. One form of heterogeneity that is seen in this situation is related
to the unique microvasculature of the hepatic acinus whereby mixed por-
tal and hepatic arterial blood enters the sinusoids in zone 1 at the center
and flows outward to drain from zone 3. Autonomic innervation of hepa-
tocytes is most dense in zone 1, as is the population of Kupffer cells. The
heterogeneity in this case is primarily related to the content of the con-
stituents of the blood and the changes that occur in the constituents as the
blood flows through the sinusoids, having compounds removed or added.
Liver damage induced by many xenobiotics is zone dependent (reviewed
in Ref. 35), with perivenous (Rappaport’s zone 3) necrosis being noted for
bromobenzine, ethanol, and CCl,. Periportal (zone 1) lesions are seen, for
example, with ally1 alcohol and digitonin. Retrograde perfusion of isolated
livers results in the lesions with these latter compounds appearing in the
perivenous zone, thus potentially implicating oxygen tension as an impor-
tant factor. Drug metabolism is differentially regulated in zone 1 and 3,
and chronic changes in blood flow are known to alter enzyme profiles.
Heavily oxygenating blood or perfusing the liver with a predominantly
arterial supply results in zone 1 cell types encroaching into the central
zone, with zone 3 cell characteristics decreasing as a proportion of the cell
population. Similarly, a reduction in chronic oxygen or arterial blood flow
perfusion leads to the reversed situation, with zone 3 population expand-
ing and zone 1 characteristics diminishing in proportion [29]. Despite our
personal preference for the acinus model, it should be emphasized that the
classic lobule is more readily seen in the pig, where the lobule is bordered
by connective tissue to form a distinct visual unit. This is not seen in
humans or most other mammals (reviewed in Ref. 35).
Heterogeneity, as the term is usually used, is also seen within the liver,
again most obviously at the smallest unit. Individual sinusoids show epi-
sodic flow varying from swift passage of red blood cells to the opposite
extreme of fully stagnant sinusoids. Temporary reversal of sinusoidal flow
or even circular flow around a few parenchymal cells has also been dem-
onstrated. At the most gross level, flow distribution to individual entire

lobes also shows some degree of dynamic heterogeneity which can be
affected by the hydrostatic pressures induced by gravity, specific microvas-
cular anatomical differences between the surface and deeper parts of the
liver, and by various active stimuli. The capsule of the liver receives
approximately 25% more arterial flow than deeper tissues [62]. Portal flow
distribution within liver lobes most often shows a pattern of highest flow
to the top, graduating down to lowest flow to the bottom (the dorsal side
on animals placed on a surgical table). This degree of heterogeneity of
perfusion appears to be under dynamic and multiple interacting forces [62].
The significant heterogeneity shown for flow on immediately adjacent
portions of the liver surface indicates that extreme caution is needed when
using small areas of flow determination to reflect changes to the entire
organ. The functional implications of the gross levels of heterogeneity are
not clear. However, heterogeneity does not appear to be significantly in-

creased in studies of large animals under in vivo conditions even under
conditions of low flow, norepinephrine infusion, sympathetic nerve stimu-
lation, or raised venous pressure [63-651.
It is feasible that microcirculatory heterogeneity that does not alter to-
tal flow could have toxicological significance based on the role of oxy-
gen in free-radical formation. Carbon tetrachloride induced damage is
associated with an increased sympathetic nerve activity that results in small
changes in hepatic blood flow. In the spontaneously hypertensive rat, CCl,
resulted in a much larger activation of sympathetic activity and a decreased
hepatic blood flow concomitant with significantly enhanced liver damage.
It was suggested that regional ischemia may account in part for some of
the toxic reaction to CCl, [66]. In normal cats, acute administration of
CCl, does not result in significant changes in hepatic arterial or portal
venous flow over the first 4 h when liver damage is clearly seen. Similary,
at 24 h there was no evidence for altered total hepatic flows [67]. Regional
heterogeneity of flow leading to local ischemia or hypoxia is thus suggested
to potentiate CC1,-induced damage but is clearly not a primary requirement
and does not reflect as altered total flow.
Although it is unclear if the effects are due to circulatory disruption,
it is clear that activation of sympathetic nerves during exposure to toxi-
cants can potentiate liver damage [68]. In addition, prior exposure to toxi-
cants leads to a state of liver physiology that responds to strong sympa-
thetic nerve stimulation or norepinephrine infusion by augmenting liver cell
damage. Although the effect of autonomic nervous activity in the liver and
the involvement of the hepatic circulation has not been evaluated from a
toxicological perspective, certain lines of evidence indicate that the hepatic
sympathetic nerves and circulating catecholamines can have considerable

impact, both with exacerbating acute liver damage and with potentiating
damage that has previously occurred. Foot shock stress increased sympa-
thetic activity in the liver and accelerated chemically induced liver injury
in rats [69]. Electrical stimulation of the ventral medial hypothalamus also
activates hepatic sympathetic nerves and potentiates acute liver damage
induced by CCl, [70]. Similar potentiating effects on liver damage are also
seen using prior treatment with galactosamine, with the demonstration that
enzyme markers of acute liver damage are increased during direct elec-
trical stimulation in isolated livers or in noradrenaline perfusion in livers
pretreated 24 h previously with galactosamine. Although hepatic sympa-
thetic nerves have been shown in isolated liver preparations perfused with
nonblood perfusate to release prostaglandins and cytokines from nonparen-
chymal cells, prostaglandins do not seem to be involved in the potentiat-
ing effect of nerve stimulation on acute liver injury [68]. Although the
mechanism of nerve-induced potentiation of liver damage is not known,
the effect is dependent upon extracellular calcium. The effect of autonomic
activation also may be different for acute toxicity compared to chronic
toxicity since it has been reported that exogenous norepinephrine provided
protection against chronic CC1,-induced liver damage by an unknown
mechanism [71].
D. Capillarization
A further hepatic vascular dysfunction occurs through the process known

as capillarization, where chronic exposure to toxic compounds leads to a
decrease in fenestration size with the endothelial cells resembling those seen
in capillaries of other organs. Kupffer cell concentration is demonstrated
to be reduced in capillarized sinusoids [72].
The first drug shown to alter fenestrae size was ethanol, which initially
dilates the fenestrae and may partially account for the protective effect from
atherosclerosis ascribed to low-dose ethanol consumption. Long-term alco-
hol abuse, however, leads to capillarization of the sinusoidal endothelium.
Capillarization is a reversible process so that 4 months after discontinuation
of thioacetamide, the sinusoidal fenestrations were increased and by an
additional 6 months, the basement membrane in the space of Disse dis-
appeared in rats [73].
It has been suggested that the decrease in the number and size of fenes-
trae in the endothelial cells and the appearance of basement membranes
in the space of Disse that is seen in alcoholic liver disease may cause a
disturbance in exchange of many bioactive substances between the sinu-

soidal blood and hepatocytes across the Disse space and may thereby
contribute to the pathogenesis of alcoholic liver disease [74]. An alterna-
tive hypothesis has been presented by Hickey et al. [75], who proposed
that the impaired hepatic function attributed to capillarization is not sec-
ondary to impaired access of the drug to the hepatocyte but rather to
impaired oxygen delivery to the hepatocyte. This proposal is supported by
the observation that the metabolism of oxidized drugs is impaired in cir-
rhosis whereas drug glucuronidation is relatively spared. In the healthy
liver, oxidative drug metabolism is more sensitive to hypoxic conditions
than glucuronidation [76]. Theophylline clearance was reduced in cirrhotic
rats and this reduction could be reversed to levels seen in healthy animals
by oxygen supplementation in the respired air. Oxygen supplementation did
not result in increased theophylline clearance in normal animals [75].
Although the effect of capillarization on the ability of drugs to diffuse

to the hepatocyte may be controversial, clearly the alteration of fenestrae
numbers and size has the potential to cause serious metabolic disturbances
with lipid metabolism. The fenestrated hepatic sinusoidal endothelium
serves as a sieve that separates the hepatic blood from the plasma in the
space of Disse. The fenestrations are of such a size that they act as a
barrier to the large triglyceride-rich chylomicrons, and only after the chy-
lomicron has diminished in size, secondary to triglyceride uptake in adi-
pose tissue, is the remnant chylomicron sufficiently small to pass through
the fenestrations to contact the hepatacyte (reviewed in Ref. 77). This liver
sieve serves as a site of hepatic selection and metabolism of dietary cho-
lesterol and fat-soluble vitamins. The ability of the hepatic sieve to par-
tially restrict albumin access to hepatocytes in healthy livers [78] implies
that capillarization could lead to reduced availability of protein-bound com-
pounds to hepatocytes. The disturbance of lipid and endocrine homeosta-
sis may contribute significantly to liver disease and some of the dysfunc-
tions in other organs that are seen in liver disease [77].
E. Ethanol
The relationship between acute and chronic effects of alcohol and the
hepatic circulation is not clear. In reviewing the mechanism of ethanol-
induced hepatic injury, Lieber [79] takes issue with the hypoxia hypoth-
esis proposing that alcohol leads to an increased consumption of oxygen
that results in a reduction of oxygen tension along the sinusoids to the

extent of producing anoxic injury in zone 3 of the acinus. In the litera-
ture reviewed, he indicates that the studies showing decreased hepatic
venous oxygen saturation and tissue oxygen tensions were within normal
ranges and that, in a number of studies, increased oxygen uptake was
accompanied by increased portal venous flow (secondary to increased flow
of extrahepatic splanchnic origin) such that zone 3 hypoxia was very un-
likely. Acute ethanol has been reported to result in a significant increase
in hepatic blood flow and an increase in oxygen consumption but with the
net result being an increased hepatic venous oxygen content [go].
Many of the toxic effects of ethanol may be linked to the ability of
ethanol to shift the redox equilibrium toward a reduced state. The depen-
dence of the ethanol-induced redox shift on oxygen tensions may contribute
to the selective zone 3 hepatotoxicity of alcohol. Anesthetized cats showed
no stimulation of ethanol metabolism or enhanced oxygen uptake after
acute or chronic administration of ethanol [81]. No evidence for a hyper-
metabolic state induced by chronic ethanol administration was seen in in-
nervated or acutely denervated livers. Oxidation of ethanol was estimated

to require 40-45% of normal oxygen uptake, leading to the conclusion that
oxidative processes must be suppressed during ethanol metabolism. Hepatic
lactate uptake remained unaltered when ethanol metabolism was less than
0.5 of V,, but was suppressed on an equimolar basis with ethanol me-
tabolism when ethanol metabolism rose to greater than 0.5 V,, [81].
Despite the large number of studies, beyond the scope of this review,
the blood flow responses to acute alcohol exposure vary from decreased
to increased; oxygen uptake has been reported to decrease, increase, show
no change, or have biphasic effects [82]. Some of the differences are
clearly methods dependent, as shown by increased portal flow in conscious
but not in anesthetized rats [83]. Dose and species and protocol differences
also exist. Much of the damage imposed by ethanol appears to be related
to free-radical formation since a variety of antioxidants reduce or com-
pletely prevent the ethanol-induced damage. These compounds include
vitamin E and S-adenosylmethionine [84]. The involvement of free radi-
cals in toxic reactions is discussed later.
F. Methodological Considerations
For technical reasons, many drug metabolic studies and acute toxicity
studies are carried out using isolated perfused liver preparations. A sub-
stantial body of evidence indicates that oxygen content of the perfusate can
alter the toxic reaction to drugs, and that ischemia results in activation of
LAUTT AND MACEDO
a number of autocoids released from within the liver that can have very
dramatic actions on the hepatic vasculature and metabolic functions. The
majority of isolated perfusion studies do not use a perfusate containing red
blood cells, so that the PO, of the blood reaching zone 1 is excessively
high whereas the PO, of blood exiting zone 3 is abnormally low compared
with in vivo levels. Similarly, most studies do not perfuse through the
hepatic artery, thus eliminating a normal regulatory mechanism designed
to produce adequate distribution of blood throughout the liver.
Additional concerns related to studies of the interactions of metabolism,
toxicity, and blood flow are based on the fact that vasoconstriction within
the liver normally will result in an increase in portal pressure, but portal
flow will not decrease [2]. If the vasoconstriction occurs at postsinusoidal
sites, the consequence will be an elevated intrahepatic pressure, with si-
nusoids being prevented from passive collapse. In contrast, in most per-
fusion studies, an elevation of intrahepatic vascular resistance occurs in a
constant-pressure perfusion, and the result is that vasoconstriction results
in a decrease in hepatic blood flow. Intrahepatic pressure will not rise and
it is anticipated that the decreased flow within this extremely low-pressure
circuit would result in increased heterogeneity of perfusion. Pharmacoki-
netic studies carried out in such preparations must be interpreted with
caution. For example, increasing hepatic extraction seen with increased
blood flow could merely represent increased sinusoidal perfusion of sinu-
soids previously underperfused.
The primary limitation of in vivo studies is related to the need to use
anesthetics. Anesthetics, such as halothane, interfere with normal hepatic
vascular regulation [49-521. Increased portal flow is seen in response to
oral ethanol in conscious but not in anesthetized animals [83]. Although
some anesthetics are clearly hepatotoxic, such as halothane, other anesthet-
ics appear to have less interactions; but all of them clearly produce some
abnormal functioning [49].
Stress results in alterations of hepatic circulation and hormonal milieu
which may have considerable significance in toxicological studies. It has
been demonstrated that activation of sympathetic nerves leads to potentia-
tion of toxicant-induced liver damage discussed earlier. It is known that
surgery results in significant disturbance of gastrointestinal tract motility
and blood flow, which returns to normal only after several days [85]. The
increasingly common use of short-term anesthesia to instrument an animal
followed by studies carried out within several hours of recovery from the
anesthesia incorporates most of the disadvantages of both anesthetized and
unanesthetized preparations. These studies should be carefully evaluated for
comparison with results obtained after several days of recovery.
111. FREE RADICALS AND ANTIOXIDANTS
From previous sections it becomes clear that regional ischemia leading

to hypoxia can potentiate the hepatotoxic effects of a variety of compounds.

Similarly, a number of stimuli that are reported to increase microvascular
perfusion heterogeneity, such as stress and sympathetic nerve activation,
are capable of potentiating hepatotoxins. Kupffer cell activation, either by
drugs or by prior administration of endotoxin, leads to microvascular dis-
turbances, and prevention of such disturbances offers protection against a
variety of toxicants [86-881. Although these various observations cannot
uniformly be directly linked to free-radical formation, many can.
Several recent reviews can be consulted for specific references [89-921.
A broad definition of a radical is that it is a molecule or ion containing
an unpaired electron. Most radicals are extremely reacitve and undergo
reaction in which the unpaired electrons become paired; some, however,
are relatively stable and have long half-lives. The reactivity of radicals lies
in the speed and affinity with which the unpaired electron participates in
covalent bonding. Often the interaction of one radical leads to the genera-
tion of a series of other steps of radical formation prior to final pairing.
Activation of oxygen for participation in metabolic pathways results in the
reactive radical intermediates, the superoxide anion radical, hydrogen per-
oxide, and the hydroxyl radical.
A number of enzymatic systems have evolved that can scavenge or
eliminate excess radicals from metabolically active biological tissue. Most
oxidative metabolism occurs within mitochondria which also serves as the
major intracellular source of superoxide radicals. Superoxide dismutases
reduce superoxide radical to hydrogen peroxide which is further decom-
posed to water by catalase and a variety of peroxidases including glu-
tathione peroxidase. These enzymes serve as a scavenging system in which
each enzyme plays an integral role in free-radical modulation. The free-
radical scavenging systems are numerous and interactive.
Lipid peroxidation reactions can be initiated by radical species, result-
ing in chain-propagating lipid radical reactions which can release lipid
hydroperoxides and significantly alter membrane fluidity and functions [93].
A variety of hydrophobic scavengers such as vitamin E and beta carotenes
are incorporated into cellular membranes and inhibit chain-propagating
reactions in lipid microenvironments [94]. A number of glutathione-depen-
dent scavenging systems are capable of reducing lipid hydroperoxides;
however, they appear to require involvement of the hydrophobic scaven-
gers in order to transfer the reagents from the lipid membrane to the glu-
tathione activity which is represented by soluble enzymes.
Antioxidant mechanisms also operate effectively in the hydrophyllic tis-

sue environment. The oxidation of extracellular, cellular, and membrane-
bound proteins can occur by a number of the strong oxidants generated
by radical reactions. Molecules such as ascorbic acid, cysteine, and reduced

glutathione all play a role in the prevention of this oxidation and the re-
generation of normal protein structure.
A number of oxidants or oxidant-potentiating compounds and antioxi-
dants are unwittingly ingested with normal and industrial society-modified
diets, and the relative dietary intakes of these compounds may well ac-
count for much of the individual variability in toxicant impact. Lists have
been prepared of ingested compounds that are thought to increase lipid
peroxidation [95]. This includes diets high in polyunsaturated fatty acids.
Diets that are extremely high in polyunsaturated fatty acids, as a result of
inappropriate attempts to modify the levels of saturated fatty acids in the
diet. have led to increased concentrations of the polyunsaturates in cell
membranes and increased oxidant products of these fatty acids. Elevated
levels of peroxidized polyunsaturated fatty acids can be readily prevented
by administration of vitamin E or vitamin C. High polyunsaturated fatty

acid content in the diet has been associated with potentiation of ethanol-
induced damage and cell death produced by carbon tetrachloride and other
toxins [%-991. Lipid peroxidation has also been attributed with the changes
in surface receptors for a variety of hormones in the liver and peripheral
tissues including insulin, glucagon, and epidermal growth factor [loo,1011.
Treatment with antioxidants decreases the triglyceride accumulation in the
liver after acute ethanol and carbon tetrachloride administration [ 102,1031.
Patients with chronic liver disease have a high incidence of systemic endo-
toxemia which may be anticipated to result in oxygen radical formation
[88] and to contribute to general systemic deterioration.
The relationship of hepatic anoxia or ischemia to oxygen-derived free
radicals has been clearly demonstrated in ischemia-reperfusion injury
[104-1061. Although the duration of time required to show this sort of
ischemia-reperfusion injury is not well delineated and it is unclear whether
such effects would occur as a result of regional ischemia in small zones
of the liver, overall antioxidant status and oxidant load will clearly impact
on the tissue damage induced by oxidant-producing toxicants.
S-Adenosyl-L-methionine (SAMe) is a metabolite in the trans-sulfuratin
pathway for the metabolism of methionine. This pathway, chiefly in the
liver, utilizes over 70% of dietary methionine and is responsible for the
synthesis of polyamines, cysteine, glutathione, and taurine, as well as a
large number of methylated molecules [107,108]. Among the methyl group
acceptors are proteins, phospholipids, DNA, RNA, histones, a number of
hormones, and creatine. In the process of methylation, SAMe is converted
to S-adenosyl-homocysteine which is further degraded to adenosine. Note

that our ciurrent hypothesis for the origin of adenosine involved in the
regulation of the hepatic arterial buffer response is through this pathway.
SAMe is currently under extensive clinical trial for a surprising range of

clinical conditions including the treatment of neuropsychiatric diseases,
degenerative diseases, cholestasis. and chronic liver disease of a variety
of etiologies. The production of SAMe in cirrhosis is reduced to approxi-
mately 30% of normal [109]. Exogenous SAMe appears not only to cor-
rect the plasma deficiencies of choline and cysteine, but may also correct
other hepatic methylation processes [ 1 lo]. Parenterally administered SAMe
antagonized liver damage in rodents produced by D-galactosamine [ 1 1 11 or
paracetamol [112], and prevented damage or accelerated recovery from
steatosis produced by choline deficiency [113] or alcohol [114]. Hexa-
chlorobenzine is a worldwide environmental pollutant known to be a po-
tent hepatotoxic compound, causing a type of porphyria characterized by
accumulation in the liver of phorphyrins with a high number of carboxy-
lic groups. Hexachlorobenzine has been shown to reduce stores of the
potent antioxidant glutathione, and administration of SAMe offers signifi-

cant protection against hexachlorobenzine [ 1 151. Whether the protective
effect is related to restoration of glutathione stores or to restoration of
methylation or to the combination of antioxidant effects is not clear.
Other potent antioxidants have been demonstrated in a number of mod-
els to protect against a variety of hepatic insults that appear to be second-
ary to radical formation. Primary among these is vitamin E, which has
been shown to be protective against carbon tetrachloride [ 1161. Beta caro-
tene is reported to have a considerably improved antioxidant capacity in
conditions of low oxygen partial pressure including ischemia [ 1 171.
Although ischemia is shown to potentiate toxic effects of agents believed
to produce hepatic dysfunction secondary to radical formation, a direct
contributory role of total or regional ischemia in toxic reactions to xeno-
biotics and protective or restorative effects of increased arterial blood
supply remains unevaluated.
ACKNOWLEDGMENTS
Manuscript preparation was by Karen Sanders. Research of the authors

that appears in this review has been supported by the Medical Research
Council of Canada and the Heart and Stroke Foundation of Manitoba.
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Hepatic Circulation and Toxicology

Article in Drug Metabolism Reviews · February 1997

Wayne Lautt M Paula Macedo

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HEPATIC CIRCULATION AND

Monte da Caparica 2825, Portugal

I. NORMAL PHYSIOLOGY ............................................. 370

*Contributed in honor of Gabriel L. Plaa, Ph.D.

Copyright 0 1997 by Marcel Dekker, Inc.

111. FREE RADICALS AND ANTIOXIDANTS ....................... 387

References .................................................................. 390

sorption of most xenobiotics, and the systemic circulation. The biological

compared to the parenchymal cells which, on average, are in contact with

bypass the liver.

tion with the animal responding as if it had been subjected to a massive

with passive changes, in contrast to the changes in resistance or pressure

Hepatic arterial blood flow is affected by circulating vasoactive com-

appropriate dilator stimuli [14]. A variety of studies have since supported

arterial bufSer response (HABR), which is the inverse response of hepatic

sylhomocysteine; the former compound is available in the liver in very

of the hepatic artery. The effect of manipulations of hepatic S-adenosyl-

regulation, which is the intrinsic ability of a blood vessel to minimize

D. Hepatic Circulation and Oxygen Supply

The hepatic arterial buffer response is a sufficiently powerful response

hepatic artery is not directly controlled by hepatic oxygen supply or de-

During hemorrhage, generalized arterial constriction occurs with the no-

when the buffer response is successfully activated to lead to an increased

does produce increased shear stress at the site of vasoconstriction, lead-

observations). The use of suppressors of other endogenous affectors of

11. TOXICOLOGY AND HEPATIC CIRCULATION

Hepatic clearance of many drugs is blood flow dependent. Although not

stream. Of equal importance, in order for the endocrine gland to afford

tients with a surgical portacaval shunt or endogenous portal systemic

portacaval shunt leads to hepatic atrophy and reduced levels of cytochrome

been attributed with at least partially accounting for nephrotoxicity. The

thane, enflurane, isoflurane, thiopental, and fentanyl when administered

in determining hepatotoxicity with mild hypothermia (32"-34"C) preventing

adenosine, which is produced by an ischemic or hypoxic liver, is an ef-

A number of toxins, seen in plants consumed as herbal remedies or teas

and dacarbazine produce hepatic veno-occlusive disease primarily as a

It is possible that glutathione exported from hepatocytes may serve a pro-

Heterogeneity of blood flow occurs at different levels within the liver.

onstrated. At the most gross level, flow distribution to individual entire

not clear. However, heterogeneity does not appear to be significantly in-

sympathetic nerves and circulating catecholamines can have considerable

A further hepatic vascular dysfunction occurs through the process known

disturbance in exchange of many bioactive substances between the sinu-

Although the effect of capillarization on the ability of drugs to diffuse

that results in a reduction of oxygen tension along the sinusoids to the

nervated or acutely denervated livers. Oxidation of ethanol was estimated

111. FREE RADICALS AND ANTIOXIDANTS

From previous sections it becomes clear that regional ischemia leading

to hypoxia can potentiate the hepatotoxic effects of a variety of compounds.

Antioxidant mechanisms also operate effectively in the hydrophyllic tis-

by radical reactions. Molecules such as ascorbic acid, cysteine, and reduced

by administration of vitamin E or vitamin C. High polyunsaturated fatty

to S-adenosyl-homocysteine which is further degraded to adenosine. Note

SAMe is currently under extensive clinical trial for a surprising range of

potent antioxidant glutathione, and administration of SAMe offers signifi-