Observations on Predicted Brain Influx Rates of

Neurotransmitter Precursors
Effects of Tumor, Operative Stress With Tumor Removal, and Postoperative TPN
of Varying Amino Acid Compositions

AURORA M. LANDEL, PHD, CHUN-CHIH LO, MS, AND MICHAEL M. MEGUID, MD, PHD, FACS’

Effects of tumor, operative stress and tumor removal, and postoperative TPN of varying amino acid
compositions on brain levels of tryptophan or tyrosine as predicted by their brain influx rates were studied
in normals and in malnourished cancer patients. Concentrations of the large neutral amino acids (LNAA)
were determined in patients before and after tumor removal, and in postoperative patients before and
after receiving either a standard TPN solution (STD-TPN), or a branched-chain amino acid solution
(BCAA-TPN). The LNAA were altered in all groups versus normals. Brain influx rates showed the
following: (1) in preoperative patients, predicted brain tryptophan levels were below normal (P< 0.001),
whereas tyrosine levels were within or above normal; (2) no significant differences between pre- and
postoperative tryptophan or tyrosine levels; (3) postoperative STD-TPN did not change predicted brain
tryptophan concentration from preinfusion values, but BCAA-TPN decreased it (P< 0.001), underscoring
the common transport carrier, and (4) preinfusion predicted brain tyrosine levels were decreased (P< 0.001)
by both types of TPN solutions. These results imply low substrate levels for brain serotonin and cate-
cholamine synthesis, possibly affecting functions dependent on their control.
Cancer 59:1192-1200, 1987.

T HE USES AND BENEFITS of total parenteral nutrition

(TPN) are generally well known. However, during
administration of TPN, homeostatic mechanisms con-
trolling plasma nutrient levels and feeding behavior are
overridden, altering the synthesis of the monoamine neu-
rotransmitters (serotonin and catecholamines) whose
synthetic rates in the brain are dependent on circulating
peripheral plasma concentrations of tryptophan (Trp) and
tyrosine (Tyr).’-’ Fernstrom and Wurtman6 have shown
that the brain levels of Trp (or Tyr) correlated directly
with the ratio of the concentration of plasma Trp (or Tyr)
to the sum of the concentrations of plasma leucine (Leu),
isoleucine (Ile), valine (Val), phenylalanine (Phe), and Tyr
(or Trp). These amino acids, together with the other large
From the Department of Clinical Nutrition, Division of Surgery, City
of Hope National Medical Center, Duarte, California.
Supported in part by City of Hope NCI Cancer Center Grant
#CA 16434 and by an Educational grant from Abbott Laboratories, North
Chicago.
Address for reprints: Michael M. Meguid, MD, PhD, FACS, Surgical
Metabolism and Nutrition Laboratory, Department of Surgery, Uni-
versity Hospital, SUNY Health Science Center, 750 East Adams Street,
Syracuse, NY 132 10.
The authors thank Mrs. Darlene Thompson for her editorial assistance,
Dr. William Hammond for helpful critique, council, advice, and com-
ments, and Dr. L. Robert Hill for assistance with the extensive statistical
analyses.
Accepted for publication October 14, 1986.
neutral amino acids (LNAA), histidine (His), methionine
(Met), and threonine (Thr), all share a common transport
carrier, and hence compete with one another for transport
across the blood-brain
Pardridge and Oldendorf’ determined the characteristic
affinity (K,) for this common carrier and the maximum
velocity (Vmax) of transport of each of these LNAA. These
kinetic constants, when used with known plasma LNAA
concentrationsin the Michaelis-Menten equation,’ enable
estimation of the brain influx (BI) of each LNAA. Fern-
strom and Faller’ demonstrated that the brain level of
each aromatic and branched-chain amino acid, when ex-
pressed as the BI rate, correlated significantly with its
plasma level relative to the concentrations of the other
LNAA.
In malnourished postoperative cancer patients, the ni-
trogen accretion effects of TPN regimens containing var-
ious amino acid compositions have been reported from
this laboratory.” When further analyzing data from these
studies, effectsof TPN on plasma LNAA levels were noted.
Since changes in the plasma LNAA levels could modify
the brain influx rates of each LNAA and thereby influence
their levels in the brain, we examined the effects of ( 1 )
operative stress and tumor removal, and (2) different TPN
regimens on Trp and Tyr influx rates across the blood-
brain barrier in cancer-bearing patients. The potential ac-

1192
No. 6 PRECURSORS Landel et al.
TPN EFFECTON NEUROTRANSMITTER - 1193

SEQUENCE OF EVENTS PATIENTS SAMF'LED COMPARISONS MADE

Before Operation
OOG ( n = 2 3 ) ; TPNG' (n=10)

Pre-op ( P R E ) n=33
Operat ion

/------
'2. vs
Post-op (POST) n=40

2nd Postoperative Day TPNG' ( n = 1 0 ) ; TPNG2 (n=30)

40 ( T P N G ~+ T P N G ~ )
I
Randomi zed
No( n=8
TPN) -I 32 PRE-TPN

S TD-TPN BCAA-TPN
N=15 N=l7 PRE-TPN

Start TPN
I I vs
OST-TPN
I
I
7 days TPW

I I I
14 days TPW

Day 15 = End of Study c

FIG. I . Schema indicating origin of amino acid samples used in patient groups as indicated in Figures 4A and 4B. Correlation between patient
groups and timing of sample procurement. Patients in the POST group were randomized to either standard TPN (STD-TPN, N = 15) or branched
chain amino acids (BCAA-TPN, N = 17): these included the 10 patients noted as TPNG' which are also included in the PRE group.

tion of these effects upon the availability of brain Trp and
Tyr for serotonine and catecholamine syntheses and their
relevance to the early reduction of food intake, often seen
in cancer-bearing patients,I also are considered.
Materials and Methods
Patient Population
As in our previous report" in which patients with gas-
trointestinal (GI) or genitourinary (GU) tract cancer were
studied, we used venous total plasma amino acid profiles
determined from the following: Operation Only Group
(OOG), 23 patients with GI or GU cancer, 9 women and
+
14 men, aged 36 to 76 years; Operation TPN (TPNG),
40 patients (Fig. 1) who underwent resections of a GI (n
= 29) or GU (n = 11) cancer (32 received TPN postop-
eratively), 22 were women and 18 were men, ages 22 to
79 years.
Patients in both groups were moderately malnourished
according to the following criteria: weight for height, tri-
1194 CANCERMarch 15 1987 VOl. 59

TABLE
1. Composition of the STD-TPN and BCAA-TPN Mixtures been described in detail.I4 The indications for providing
Constituents STD-TPN BCAA-TPN TPN were as follows: (1) the presence of malnutrition as
defined above; and/or (2) an operative procedure which
Amino acid 4.25% 3.5% precluded early resumption of oral intake and which re-
Fat 10%-20% 10%-20%
Dextrose 15%-25% 15%-25% quired prolonged bowel rest. The final study blood sample
LNAA (g/U was obtained before the patient started any oral intake,
Leu 4.05 3.06 at which point the patient was taken off the study. After
Ile 3.10 4.75
Val 3.40 7.2 1 adequate oral intake was resumed, TPN was stopped.
Phe I .90 1.09
Trp 0.75 0.42 TPN Regimens
TYr 0.22 0.15
His 1.30 0.74
Met 1.70 0.98 The compositions of the two solutions and their dis-
Thr 2.30 1.30 tinguishing features are shown in Table 1 . Patients re-
BCAA:non-BCAA
BCAA
25:75
1.06%
45:55
1.50%
*
ceived an average of 34 14 Kcal and 0.2 ? 0.01 g ni-
trogen (N)/kg/day(M f SE). Thirty percent of the calories
STD-TPN: standard total parenteral nutrition; BCAA-TPN:branched- were provided as fat and standard amounts of vitamins
chain amino acid solution of total parenteral nutrition; LNAA: large and minerals were added to both solutions as previously
neutral amino acids; Leu: leucine; Ile: isoleucine; Val: valine; Phe: phe-
nylalanine; Trp: tryptophan; Tyr: tyrosine: His: Histidine: Met: methi- described.” AU patients took nothing orally while on TPN.
onine: Thr: threonine.
Analytic Method
ceps skin-fold thickness, and mid-upper arm muscle cir- Fasting venous blood samples were obtained between
cumference, all less than nintieth percentile; a recent 6:OO AM and 8:OO AM. Total plasma amino acidsI6 were
weight loss greater than 10%;and posthydrational serum determined on a protein-free filtrate, following precipi-
albumin less than 3.5 g/dl on admi~sion.’~ The patients’ tation with sulfosalicylic acid, by an automated method
demographic and surgical characteristics have previously using a Beckman 121 MB Amino Acid Analyzer (Beck-

FIG.2. Effect of ( I ) tumor presence

and (2) operative stress and tumor re-
moval on plasma large neutral amino
acid levels. PRE group, n = 23, 0 ;and
POST group, n = 40,i 3.Normal range
of amino acid in fasting plasma, El. f :
amino acid level, mean & SE; compar-
isons between preoperative and post-
operative groups are significant at P
< 0.001 for all AA except Tyr (Pi0.01)
and Phe (NS). The number in the cross-
hatched area represents the percentage
of patients with amino acid within the
normal range. The number above the
crosshatched area represents the per-
centage of patients with amino acid val-
ues above the upper limit of the normal
range, and the number below the cross-
hatched area represents the percentage
of patients with amino acid values below
the lower limit of the normal range.

TYR TRY LEU ILE HIS MET THR

No. 6 PRECURSORS* Landel et al.
TPN EFFECTON NEUROTRANSMITTER 1195

PHENYLALANINE TYROSINE TRYPTOPHAN

STD-TPN
1111 1751 111
60% IwTr 4 1,')
0C44-TPN
1171 191

68% 90% 91%

STD-TPN BC4A-TPN STD-TPN BCA4-TPN

1125-

1050 -

975-

900 -

-1 7 14 -1 7 14
-I
33% 4.3% 55%

-1 7 14
DAYS ON TPN
;4

-1
6 7

I 14
1
:9
.1
5f*27%14~
7 14 -1 7
7j
~p"
14
-5
-
,
-
825~

E 750-
3
0
2 675-

THREONINE

200 -

180 -
160 -
I I
- 140-

5 120- HISTIDINE
E STD-TPN BC44-TPN ST D -TPN 0CAA -TPN

-*
-
0
100-
0 107.46% ! *u 0 0 I 7% 9su 01% 20% 7C-b $..I
olzo*. I 7
0
14
I'Z%
-1
'97%14a 1
DAYS ON TPN

FIGS. 3A-3C. (A, top left) Effect of the TPN on plasma levels of ar-
omatic amino acids, (B, top right) branched-chain amino acids and (C,
bottom) other LNAA in POST (n = 32) before TPN and on the seventh
and fourteenth days of TPN infusion.3 : amino acid concentration, mean
+_ SE. Percentages of patients having amino acid values within normal

-1 7 14 -1 7 14
-
0%

-1
0

7
0

14

DAYS ON TPN
[.a*
-1 7
9,"

14
range are the numbers in crosshatched areas; those with amino acid
values above and below normal range are the numbers above and below
crosshatched areas, respectively.

man, Palo Alto, CA). Total plasma Trp was determined,

and not just the free portion, because total plasma Trp
usually provides a closer estimate of actual Trp concen-
tration available to the brain.
The normal amino acid ranges in our laboratory were
determined on samples from 28 healthy volunteers and where: V,,, = 33 nmol/g/minute, maximum velocity
of uptake of Trp; [AAIT, = plasma concentration of tryp-
are shown in Figures 2 through 4A and 4B. Normal range
was determined as follows: values of each individual tophan and [AA] = plasma concentration of each LNAA
amino acid were measured and the lowest and highest competitor from patient's amino acid profile; KmTV = 0.19

values constituted the limits of the range. Venous blood mmol/ 1, binding constant for tryptophan; K, = binding
samples also were analyzed for albumin, blood urea ni- constant in mmol/l for each LNAA competitor (Tyr
= 0.16, Phe = 0.12, Leu = 0.15, Ile = 0.33, Val = 0.63,
trogen (BUN), creatinine, and electrolytes using a se-
His = 0.28, Met = 0.19, and Thr = 0.73. For the calcu-
quential multiple analyzer and computer (SMAC, Tech-
lation of BI-Tyr, V,, for Tyr = 46 and K, = 0.16).
nicon, Tenytown, NY)but only data germane to this re-
It may be argued that this method of calculation is not
port are given.
appropriate for humans since the binding constants were
derived from rat data. However, these constants were used
Calculation to Estimate Brain Tryptophan
by Higashi et al.l8 to compare predicted BI rates of LNAA
and Tyrosine Levels
to measured (CSF) levels of LNAA in patients with hepatic
Analysis of the actual brain levels of tryptophan and encephalopathy. His observations suggested that accel-
Tyr in humans is hampered by the problem of sample erated transport of neutral amino acids into the brain
availability. However, it is possible to estimate these levels, may be involved in hepatic encephalopathy, and his hy-
based on the data of Partridge and Oldendorf,' from the potheses are in accord with other In the absence
BI rate (nmol/g/minute): of binding constant values for humans, we have followed
1196
FIGS. 4A AND 4 8 . Comparison of the effect of varying the amino acid composition of TPN on (A, left) tryptophan availability (BI-Trp) in the
brain for serotonin synthesis. and (B, right) tyrosine availability (BI-Tyr) in the brain for catecholamine synthesis, in postoperative cancer patients.
Parenthetic numbers at top are the number of patients studied at each of the times indicated along the baseline; points and vertical bars are M f SE
of B1-Trp and BI-Tyr, respectively.Crosshatched areas: range of values in normals. Percentages: percent of patients with values above, below, or
within the normal range.
the precedent set by Higashi et al., and have used rat
constants in humans because the measured results com-
pared well with the predicted values.
Experimental Design
To assess the effects of the presence of cancer (and a
modest degree of associated malnutrition) amino acid
profiles of samples obtained preoperatively from all pa-
tients in the OOG (n = 23) and from patients in the
TPNG’ were compared to the normal values in our lab-
oratory. The effects of tumor removal (and its accom-
panying physiological stress) were assessed by comparing
amino acid profiles in samples obtained on the second
postoperative day from 40 patients (10 from TPNG’, 30
from TPNG2) to both the preoperative samples and to
normals.
To study the effects of differing TPN regimens, 40 pa-
tients (TPNG’ and TPNG2) were randomized postoper-
atively to receive either standard TPN solution (STD-
TPN) or branched-chain amino acid TPN solution
(BCAA-TPN). Eight patients in this group, five on STD-
TPN and three on BCAA-TPN, began to eat earlier than
anticipated and required TPN for less than 7 days and
therefore became ineligible. Amino acid profiles deter-
mined in blood samples obtained on the second postop-
erative day from the remaining 32 patients in the TPNG
(PRE-TPN) were compared to samples obtained after I
and 2 weeks of TPN. Seven of the 15 patients who received
1 week of STD-TPN and 8 of the 17 patients who received
CANCERMarch 15 1987 VOl. 59
1 week of BCAA-TPN resumed oral intake between the
eighth and the fourteenth days, respectively. The timing
of blood sample acquisition is shown schematically in
Figure I . Immediately after obtaining the last blood sam-
ple, TPN was discontinued.
Statistical Methods
Simple comparisons between two groups were per-
formed using a two-tailed Student’s t test for unpaired
data. Data are presented as mean ? standard error (M
k SE).
Data Analysis
The values for plasma concentration of each LNAA,
BI-Trp and BI-Tyr are generally expressed as M k SE.
However, using this method alone does not accurately
depict the real situation. For example, if 50% of a popu-
lation had values for an amino acid within the normal
range and the other 50% had values equally distributed
between below and above the normal range, then the
“mean” of the whole population would be underranged
and the two subpopulations would be erroneously con-
strued as being comparable (e.g.. see preoperative valine,
postoperative Met and Thr; Fig. 2).
To avoid this misrepresentation of our data, the values
of BI-Trp, BI-Tyr and the plasma concentrations of each
LNAA for each sample from each patient in both OOG
and TPNG were compared to the normal range for our
laboratory (cross-hatched areas in Figs. 2-4A and 4B).
No. 6 TPN EFFECTON NEUROTRANSMITTER
PRECURSORS Landel et al. - 1197

TABLE2. Predicted Brain Influx Rates of Tryptophan in Preoperative, Postoperative, and TPN-Infused Postoperative Cancer Patients

Patient groups (4 Preoperative d-l* d7 dt4

-~

PRE (23) 1.60 + 0.07 ND ND ND

POST (40) I .50 f 0.08 ND ND
PRE-TPN (32)t 1.55+0.12 ND ND
Randomized to
STD-TPN (15) 1.42+0.12 1.62 + 0.06 1.66 t 0.08
BCAA-TPN (17) 1.67 f 0.13 1.15 f 0.08 1.28 f 0.08

Normal range of predicted brain influx rate: 1.86-2.58 nmol/g/minute. t PRE-TPN: 32 patients from group POST.
* d-, refers to postoperative PRE-TPN blood samples, and is the second TPN: total parenteral nutrition; ND: not done; S T D standard; BCAA:
postoperative day; d7 and d14refer to the seventh and fourteenth days, branched chain amino acids; PRE: preoperative; POST: postoperative;
respectively, of TPN infusion. PRE-TPN: before TPN.

Amino acid levels which were found to be below the lower
limit of this normal range were considered “below nor-
mal”; values above the upper limit were considered “above
normal”, whereas intermediate values were considered
“normal.”
The percentage of values in each of these categories,
“below,” “above,” and “normal,” among patients is
shown as a number below, above, and/or within the
crosshatched areas in Figures 2 through 4A and 4B.
Results
The mean serum albumin before operation was 3.0
k 0.3 mg/dl. It did not change significantly by the second
postoperative day; it was 2.9 f 0.1 mg/dl in the STD-
TPN group and 3.0 f 0.2 mg/dl in the BCAA-TPN group
at the time of randomization, and 2.8 t- 0.1 mg/dl in both
groups after 14 days of TPN. Patients did not receive salt-
poor albumin during their hospital course, but in each
group were transfused an average of 4 U of packed cells
(1000 ml) during the first two postoperative days. Insulin
was not added to their TPN solutions.
The results of the t tests demonstrated that the predicted
brain Trp and Tyr influx rates were calculated for the 10
patients in the TPNG’ group, for the OOG, for the TPNG,
and for TPNG’ and TPNG’ separately. There were no
significant differences between the following: (1) the pre-
dicted brain Trp (Table 2) or Tyr (Table 3) of the 23
patients in the OOG group and the corresponding values
for the TPNG’ preoperatively; (b) the postoperative pre-
TPN (d-’) predicted brain Trp or Tyr influx rates for all
40 patients in the TPNG group and those for either the
TPNG’ group or the TPNG’ group. It is, therefore, rea-
sonable to assume that, had preoperative amino acid pro-
files of the TPNG’ group been available, their means for
the predicted brain Trp and Tyr influx rates would be
close to the corresponding means (1.67 f 0.16 and 3.97
+- 0.20, respectively)of the TPNG’ group for which such
data were available. We therefore analyzed the OOG
samples and the TPNG‘ samples as a single composite
preoperative group (PRE), and the TPNG’ and TPNG’
samplesas a single compositepostoperative group (POST).
The normal range for each individual plasma LNAA
in our laboratory is shown in Figure 2. The normal range
for BI-Trp is 1.86 to 2.58 nmol/g/minute, and for BI-Tyr
is 3.12 to 5.45 nmol/g/minute.
Eflect of Tumor and Operative Stress
With Tumor Removal
Plasma LNAA concentrations: The distribution of val-
ues from patients in both PRE and POST are shown in
Figure 2. The majority of patients were observed with the
following values: (1) above the normal range for only Phe
(65%in PRE; 67%in POST); (2) below the normal range
for Trp, Val, and His (78%, 52%, and 63%, respectively,

TABLE3. Predicted Brain Influx of Tyrosine in Preoperative, Postoperative, and TPN-Infused Postoperative Cancer Patients

Patient groups (n) Preoperative d-l* d7 d14

PRE (23) 4. I8 f0.20 ND ND ND

POST (40) 4.28 + 0.01 ND ND
PRE-TPN (32)t *
3.99 0.22 ND ND
Randomized to
STD-TPN (15) 4.04 2 0.18 2.81 f 0 . 1 2 2.86 2 0.26
BCAA-TPN (17) *
3.95 0.26 1.99 t 0.20 2.73 f 0.40

Normal range of predicted brain influx rate: 3.12-5.45 nmol/g/minute. t PRE-TPN: 32 patients from group POST.
* d-, refers to postoperative PRE-TPN blood samples, and is the second TPN: total parenteral nutrition; ND: not done; STD. standard; BCAA:
postoperative day; d7 and d,, refer to the seventh and fourteenth days, branched-chain amino acids; PRE: preoperative; POST: postoperative;
respectively, of TPN infusion. PRE-TPN; before TPN.
1 I98 CANCERMarch 15 1987
in PRE; 80%, 70%, and 9376, respectively, in POST); (3)
within the normal range for Tyr and Leu (65% and 70%,
respectively, in PRE; 53% and 63%, respectively, in
POST); and (4) within the normal range for Ile and Thr
(48%and 74%,respectively)in PRE, but below the normal
range in POST (73% and 60%, respectively).
For Met, there was an equal distribution of patients
with values above and within normal range in PRE (39%
and 39%, respectively), but a high percentage of patients
below normal range in POST (53%)was noted.
When our data was expressed either as the percentage
distribution of patients or the M f SE, every LNAA in
POST was lower than the same LNAA in PRE.
Predicted brain Trp and Tyr influx rates: These data
are summarized in Table 2. The PRE and POST BI-Trp
(M ? SE) were below normal ( P < 0.001). Descriptively,
most of the patients in PRE and POST had predicted
brain Trp influx rates which were below the normal range
(78% and 70%, respectively). No PRE patient had values
above the normal range.
As summarized in Table 3, PRE and POST BI-Tyr (M
& SE) were within normal values. Descriptively, the ma-
jority of the patients in both groups had predicted brain
Tyr influx rates which were above (39% and 37%,respec-
tively) or within the normal range (48% and 40%, respec-
tively).
Efects of Standard and Branched-Chain
Amino Acid-Enriched TPN
Plasma LNAA concentrations: The trend of the ob-
served changes becomes apparent when the M f SE values
of the plasma LNAA level are viewed.
This is visually verified by looking at the percentage of
patients having amino acids above, below, and within
normal range. Irrespective of the individual LNAA ex-
amined, the percentage of patients having amino acid val-
ues above, below, and within the normal range on day 7
differed from that seen before the start of TPN (Figures
3A-3C). The changes on d7 reflected the composition of
the TPN solution shown in Table 1.
As seen in Figures 3B and 3C, after administration of
either TPN solution, a significant increase in the levels of
Ile and Val ( P < 0.001) and in the levels of Met and Phe
( P < 0.01) occurred on d7 and d14. Tyrosine levels (Fig.
3A), which were within the normal range before TPN was
started, remained unchanged after administration of the
STD-TPN solution, but were below the normal range in
the majority of patients on d7 and d14 as a consequence
of giving BCAA-TPN solution ( P < 0.001). Tryptophan
levels were below normal before TPN. They remained
unchanged after BCAA-TPN infusion, but their levels in-
creased to within normal with the infusion of STD-TPN
(P< 0.001).
Vol. 59
Significant elevations of Leu, His ( P < O.Ol), and Thr
( P < 0.001) occurred on d7 and d14 after STD-TPN in-
fusion. In comparison, no significant change with BCAA-
TPN occurred: His remained below normal and Leu and
Val remained within normal values.
Predicted brain Trp and Tyr influx rates: The differences
in TPN effect from varying the amino acid concentration
of the TPN solution can be seen by looking at the mean
values of the predicted Trp and Tyr influx rates and thus
levels shown in Figures 4A and 4B. Using these values
for comparison between the effects of STD-TPN and those
of BCAA-TPN is justified, since, after infusion of either
solution, the majority of the patients had predicted Trp
and Tyr concentrations which were below normal. The
predicted availabilityof Trp in the brain was below normal
for all these patients, both before operation and after op-
eration, and before administration of TPN (Fig. 4A). After
TPN infusion, this value did not significantly change on
d7 or d14 for STD-TPN but decreased significantly for
BCAA-TPN (P< 0.001).
The predicted Tyr influx rate and hence its level in
the brain (Fig. 4B), within the normal range before TPN,
decreased significantly ( P < 0.00 1) to below normal after
7 days of either TPN solution; BCAA-TPN showed a
greater decrease. By the fourteenth day of TPN infusion,
Tyr had increased significantly ( P < 0.001) from d7 for
BCAA-TPN but remained within the d7 range for STD-
TPN. There were no significant differencesbetween STD-
TPN and BCAA-TPN values on d14.
In looking at the percentage distribution as shown in
Figure 4A, before infusion a high percentage (80% and
53% for STD-TPN and BCAA-TPN, respectively) of pa-
tients had predicted brain Trp influx rates and hence brain
values which were below normal. These percentages in-
creased on d7 and d14 after TPN infusion. The increase
was greater from BCAA-TPN (100% and 90% respec-
tively) than from STD-TPN (93%and 87%,respectively).
On the other hand (Fig. 4B), before infusion most pa-
tients had predicted brain Tyr concentrations either within
(40% and 47% for STD-TPN and BCAA-TPN, respec-
tively) or above the normal range (47%and 4 1% for STD-
TPN and BCAA-TPN, respectively). Upon infusion of
either TPN solution, Tyr dropped to levels below the nor-
mal range in all the patients on d7 and d14.
Discussion
Among amino acids, Trp is unique because at physi-
ological concentrationsit is bound to albumin.” However,
at low albumin levels (<4.1 g/dl), less than 30% of Trp is
bound to albumin.” The amount of Trp available for
transport into the brain is equal to all of the free amino
acid plus a variable fraction of the bound Trp. However,
since the fraction of bound Trp directly transported into
No. 6 PRECURSORS* Landel el al.
TPN EFFECTON NEUROTRANSMITTER
the brain exceeds the fraction represented just by the free
amino acids, the total plasma Trp and not just the free,
provides a closer estimate of the actual Trp concentration
available, because the majority of the bound Trp is
stripped off by the blood-brain bar~ier.'~ The addition of
intravenous fat (or medication) lead to binding of free
fatty acids to albumin, fascilitating the dissociation of al-
bumin-bound Trp at the blood-brain bamer and raising
brain Trp levels.24In our patients serum albumin levels
did not significantly change, and both groups received
comparable amounts of intravenous fat.
Our data show that preoperative patients with cancer
of the GI and GU tracts had altered fasting plasma LNAA
profiles when compared to normals. These amino acid
profiles were further altered by the combined stress of
operation and tumor removal, and were altered still fur-
ther by postoperative TPN of varying amino acid com-
positions.
The observed changes in the amino acid profile of the
fasting cancer patient may be due to the following: (1)
decreased food intake secondary to the anorexia associated
with cancer;" and (2) changes in the rate of protein turn-
over or exchange of amino acids between body compart-
m e n t ~ . ' ~The
, ~ ~decreased levels of each LNAA (except
Phe) in the POST group when compared to the PRE can-
cer patients may be due to the catabolic hormonal milieu
induced by the stress of the o p e r a t i ~ n ~rather
' ? ~ ~ than the
presence of a tumor, because similar observations have
been found after operation in patients without cancer.29
The elevated Phe level and the decreased Tyr level in
both PRE and POST populations suggest that the hy-
droxylation of Phe to Tyr may be impaired. This has been
directly attributed to the presence of a tumor.30In meth-
ylcholanthrene-induced sarcoma-bearing rats, recent data
from our laboratory showed that total free amino acid
concentrationswere significantly decreased in plasma and
skeletal muscle, and free amino acid profiles of liver and
spleen differed greatly from normal control. Tumor ex-
cision restored the abnormal free amino acid levels and
patterns to those of normals.31
The observed changes in the plasma LNAA concen-
trations in both the PRE and POST groups would lead
to a significant decrease (P < 0.001) in predicted brain
influx rates of Trp. The effect of the altered LNAA levels
on predicted brain Tyr concentrations was variable, al-
though the predicted BI rates remained predominantly
within normal range in both groups.
The implications of these changes for cancer-bearing
patients lie in the potential functional significance to the
brain of altered plasma LNAA levels, i.e., the decreased
Trp availability for serotonin synthesis and the variable
amounts of Tyr available for catecholamine synthesis. We
speculate that brain functions which are under serotonin
and catecholamine control might thereby be affected. One
1199
example of these is the venteromedial hypothalamus sa-
tiety center, which is under positive serotonin control,
i.e., high levels of serotonin result in satiety which is in-
hibited by n~repinephrine.~~ Decreased serotonin levels
in the cancer patient would decrease activation of the sa-
tiety center and thus increase the hunger sensation. In-
creased catecholamines would increase its activity, thereby
inhibiting hunger (possible anorexia). The net activity of
this hypothalamic component in the cancer patient would
depend on the integration of these signals and the inputs
from additional factors regulating feeding behavior (pep-
tides like cholecystokinin, enkephalins, thyrotropin-re-
leasing hormone, and others).32Indeed, in a double-blind
crossover study the effects of a single dose of Trp and Tyr
on human behavior were studied.33Tryptophan admin-
istration was found to increase subjective fatigue while
decreasing vigor and alertness. Tyrosine administration
decreased reaction time when compared to Trp.
In assessing effects of TPN, plasma obtained during
infusion of either STD-TPN or BCAA-TPN would, a
priori, be expected to contain levels of each LNAA in
direct proportion to its concentration of the infused so-
lution. Thus, Leu, Phe, Trp, and Tyr levels were higher
in the plasma of patients infused with STD-TPN than in
those with BCAA-TPN. Isoleucine and Val were in excess
in the BCAA-TPN solution, and these increases were re-
flected in the plasma of the BCAA-TPN-infused patient.
However, whereas most low PRE-TPN amino acid values
in patients were raised to or above normal levels by STD-
TPN infusion, Trp, Tyr, and His remained below normal
in the BCAA-TPN-infused patients. Phenylalanine re-
mained high in patients receiving either type of TPN. If
hydroxylation of Phe to Tyr is indeed impaired,30there
might be a need to decrease Phe and increase the amounts
of Tyr in TPN solutions. Based on the data cited above,33
this TPN compositional change might have beneficial ef-
fects on mood status in the malnourished cancer patient,
thereby enhancing appetite.
The administration of STD-TPN to cancer patients af-
ter tumor removal did not correct the existing predicted
low brain concentrations of Trp needed for serotonin
synthesis; BCAA-TPN administration exacerbated the
deficit. As regards Tyr, needed for catecholamine synthe-
sis, infusion of either TPN lead to a fall from normal to
below normal for predicted brain levels.
Our observations on BCAA-TPN agree with those of
Wahren et al. l9 who found that BCAA-enriched solutions
decreased the brain uptake of Trp and Phe in cirrhotic
patients. Whereas this might be the desired result in cir-
rhotic patients, it may not be so in other disease states.
For example, decreased Tyr availability might adversely
affect peripheral sympathoadrenal cells whose catechol-
amine output may be important for normal cardiac and
peripheral vascular function.34
1200 CANCERMarch 15 1987
In our cancer patients, the initial purpose of infusing
BCAA-enriched crystalline amino acids was to enhance
nitrogen accretion, a nutritional objective that was real-
'
ized. However, the resulting plasma amino acid aber-
rations observed, as reported here, should lead to further
consideration of other biochemical effects which TPN so-
lutions have on other organ function(s).
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