MINIREVIEW

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Oxidative Stress and First-Line Antituberculosis Drug-Induced

Hepatotoxicity
Wing Wai Yew,a Kwok Chiu Chang,b Denise P. Chana

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a
Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China
b Tuberculosis and Chest Service, Department of Health, Hong Kong, China

ABSTRACT Hepatotoxicity induced by antituberculosis drugs is a serious adverse

reaction with significant morbidity and even, rarely, mortality. This form of toxicity
potentially impacts the treatment outcome of tuberculosis in some patients. Cover-
ing only first-line antituberculosis drugs, this review addresses whether and how oxi-
dative stress and, more broadly, disturbance in redox homeostasis alongside mito-
chondrial dysfunction may contribute to the hepatotoxicity induced by them. Risk
factors for such toxicity that have been identified, in addition to genetic factors,
principally include old age, malnutrition, alcoholism, chronic hepatitis C and chronic
hepatitis B infection, HIV infection, and preexisting liver disease. Importantly, these
comorbid conditions are associated with oxidative stress and drugs related to anti-
oxidants, especially those for management of mitochondrial dysfunction. Thus, the
shared pathogenetic mechanism(s) for liver injury might be in operation due to
disease-drug interaction. Our current ability to predict, prevent, or treat hepatotoxic-
ity (other than removing potentially hepatotoxic drugs) remains limited. More trans-
lational research to unravel the pathogenesis, inclusive of the underlying molecular
bases, regarding antituberculosis drug-induced hepatotoxicity is needed, and so is
clinical research pertaining to the advances in therapy, with antioxidants and be-
yond. The role of pharmacogenetics in the clinical management of drug-induced
hepatotoxicity also likely merits further evaluation.
KEYWORDS drugs, hepatotoxicity, tuberculosis

I nappropriate oxidative stress (and nitrosative stress) generally results from an imbal-
ance in the production of reactive oxygen species (ROS) and reactive nitrogen species
(RNS), alongside their reduced elimination and/or the suboptimal response of antioxi-
dative defense (1, 2) (Table 1). Oxidative stress is exogenous or endogenous in origin.
Exogenous oxidative stress can be induced by drugs, and endogenous oxidative stress
is inherently associated with some conditions and diseases (1). Inappropriate oxidative
stress is harmful to the host and may result in organ injury (1, 2). Covering only first-line
antituberculosis drugs, this review addresses whether and how oxidative stress may
contribute to antituberculosis drug-induced hepatotoxicity, which has been a long-
standing concern in the treatment of tuberculosis (3, 4).
Accepted manuscript posted online 21 May
OXIDATIVE STRESS AND DRUG-INDUCED HEPATOTOXICITY 2018
The liver is an important organ with substantial vulnerability to the deleterious effects Citation Yew WW, Chang KC, Chan DP. 2018.
Oxidative stress and first-line antituberculosis
of oxidative stress (1, 2). Mitochondria, microsomes, and peroxisomes of hepatocytes are drug-induced hepatotoxicity. Antimicrob
associated with the production of ROS, which impact the regulation of signaling pathways, Agents Chemother 62:e02637-17. https://doi
including peroxisome proliferator-activated receptor alpha (PPAR␣) governing fatty acid .org/10.1128/AAC.02637-17.
oxidation, and mitogen-activated protein kinase (MAPK) and related stress-sensitive kinases Copyright © 2018 American Society for
Microbiology. All Rights Reserved.
associated with proapoptosis. Furthermore, in Kupffer cells, oxidative stress might induce
Address correspondence to Denise P. Chan,
the elaboration of cytokines, such as tumor necrosis factor alpha, that contribute to the denisechan@cuhk.edu.hk.
progression of tissue inflammation and cell apoptosis. In hepatic stellate cells, oxidative

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TABLE 1 Some reactive oxygen species, reactive nitrogen species, and components of
antioxidative defense
Category Substance
Reactive oxygen species Hydroxyl ion (OH⫺)
Hydroxyl radical (·OH)
Peroxide (·O22⫺)
Hydrogen peroxide (H2O2)
Superoxide anion (·O2⫺)
Singlet oxygen (1O2)

Reactive nitrogen species Nitric oxide (NO)

Nitrogen dioxide (NO2)
Peroxynitrite (ONOO⫺)
Nitrosoperoxycarbonate (ONOOCO2⫺)

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Antioxidative defense Nitric oxide (NO)
Glutathione transferase (GST)
Glutathione peroxidase (GTPx)
Catalase (CAT)
Superoxide dismutase (SOD)
Nuclear factor-erythroid 2 related factor (Nrf2)
Beta-carotene
Ascorbic acid (vitamin C)
Alpha-tocopherol (vitamin E)
Selenium
Zinc

stress-mediated lipid peroxidation can lead to increased collagen synthesis. Complex cross
talk between oxidative stress (nitrosative stress) and immune responses has been sug-
gested to play a critical role in the pathogenesis of liver injury (Fig. 1). In humans and other
mammalian species, a sophisticated antioxidative system to preserve redox homeostasis is
found in the liver (1). However, when perturbation of the homeostasis is to such a degree
that it culminates in overwhelming oxidative stress that challenges the liver of the host,
jeopardy of the organ status ensues due to damage to intracellular targets, notably lipids,
proteins, and DNA, and there is an adverse impact on key signaling pathways for the

FIG 1 A simplified representation of the pathogenesis of drug-induced hepatotoxicity. Oxidative stress and mitochondrial dysfunction
are important mechanisms contributing to drug-induced hepatotoxicity. Genetic polymorphisms associated with drug metabolism,
oxidative stress, and immune response interact in an intricate way, with conditions/diseases associated with oxidative stress per se,
leading to cellular inflammation, apoptosis, and necrosis, which manifest as histopathological changes of hepatotoxicity. The dashed
line indicates possible interaction between immunological response and oxidative stress.

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FIG 2 Metabolism of isoniazid in the liver. Isoniazid is metabolized by acetylation to acetylhydrazine and
diacetylhydrazine. Acetylhydrazine can be hydrolyzed further to become isoniazid hydrazine, which also
results from the hydrolysis of isoniazid itself. Isoniazid hydrazine is toxic to hepatocytes, and so are the
more toxic reactive metabolites further derived from it through the activities of cytochrome P450
enzymes.

maintenance of optimal biological functions of the liver involved, and even other organs
(2). Some examples of drug-induced hepatotoxicity associated with oxidative stress are as
follows. It has been shown that acetaminophen-induced hepatotoxicity is related to its
metabolic derivative, N-acetyl-p-benzoquinone imine, which depletes glutathione (GSH)
from cellular storage and promotes protein adducts in mitochondria. Mitochondrial dys-
function and oxidative stress thus ensue, with subsequent activation of c-jun N-terminal
kinase (JNK) and ultimate induction of mitochondrial membrane permeability transition
(MPT). Apoptosis-inducing factor and endonuclease G are then released, leading to nuclear
DNA fragmentation and programmed necrosis (5, 6). Also, in diclofenac-induced hepato-
toxicity, mitochondrial dysfunction and oxidative stress are now viewed as likely underlying
mechanisms based on some molecular evidence (7).

OXIDATIVE STRESS AND ANTITUBERCULOSIS DRUG-INDUCED HEPATOTOXICITY

Hepatotoxicity induced by antituberculosis drugs might result in significant mor-
bidity and, rarely, even mortality (8–10). Such toxicity also hampers patient adherence
to therapy and could negatively impact the treatment outcome of patients. Isoniazid,
pyrazinamide, and rifampin, the three key first-line antituberculosis drugs, have poten-
tial hepatotoxicity. Both dose-dependent and hypersensitivity/idiosyncrasy mecha-
nisms are at play, with either one often predominating, as reported, though with some
disparity (8, 10). For example, for isoniazid, the idiosyncratic mechanism is generally
favored, and for pyrazinamide, the dose-dependent mechanism is usually preferred.
The association of oxidative stress with isoniazid-induced hepatotoxicity appears
to be reasonably well understood (8–10). As shown in Fig. 2, isoniazid is metabo-
lized by N-acetyltransferase 2 (NAT-2) to acetylhydrazine and diacetylhydrazine.
Diacetylhydrazine is nontoxic and is readily eliminated from the body of the host.
However, the acetylhydrazine metabolite of isoniazid can be further hydrolyzed to
the hepatotoxic isoniazid hydrazine, and so can isoniazid itself. These hydrolysis
pathways are more activated in subjects with a slow-acetylator phenotype (with any
two of the several alleles of the NAT2 gene). A meta-analysis demonstrates that slow
acetylators have an increased risk of antituberculosis drug-induced liver injury (11).
Another study involving a mixed-ethnicity patient group has also demonstrated the
association after controlling for possible confounding effects by ethnicity (12).

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Isoniazid hydrazine can be further metabolized by cytochrome P450 (CYP) 2E1

isoenzymes to reactive derivatives/metabolites with greater toxicity (Fig. 2). Sub-
jects with CYP2E1 c1/c1 alleles and higher enzymatic activity have been shown to be
more prone to isoniazid-associated hepatotoxicity (13, 14). GSH, an important
antioxidant, protects against oxidative damage by furnishing a thiol (-SH) group for
conjugation with the reactive metabolites. Deficiency in glutathione S-transferase
(GST) activity because of homozygous null mutations at GSTM1 and GSTT1 loci can
influence susceptibility to isoniazid-induced hepatotoxicity. In a case-control study,
the frequency of GSTM1 null mutations in subjects with hepatic dysfunction in-
duced by an antituberculosis drug was found to be twice as common (15). In
another study, the occurrence of hepatic dysfunction in patients with tuberculosis
was 2.6 times more likely in those with GSTT1 null mutations (16). Earlier animal

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experiments have shown reduced levels of GST and other antioxidative enzymes
after the administration of isoniazid hydrazine (9). In a recent study using isolated
liver mitochondria from rats, oxidative stress and mitochondrial dysfunction in-
duced by isoniazid have been well shown (17). Another study in mice has estab-
lished the role of micro-RNA-122 in oxidative stress-related liver injury by isoniazid
(18). It has been suggested that isoniazid toxicity might be mediated through an
interaction with electron transport chain, lipid peroxidation, mitochondrial mem-
brane potential change, and cytochrome c extrusion, resulting in detrimental cell
signaling (17). As there have been some data regarding a better correlation of
higher severity of isoniazid-induced hepatotoxicity with RNS than with ROS, per-
oxynitrite (ONOO⫺) generation and mitochondrial dysfunction probably have sig-
nificant contributions to such toxicity (19, 20).
Rifampin alone has low potential for hepatotoxicity (6), but it exhibits additive or
even synergistic hepatotoxicity when used with isoniazid concomitantly in treating
tuberculosis (21). Pregnane X receptor (PXR), a member of the nuclear receptor
superfamily of ligand-dependent transcription factors, can be activated by rifampin,
resulting in the upregulation of phase I and phase II drug-metabolizing enzymes,
including CYPs and GSTs, as well as drug/substrate transporters, such as ATP binding
cassette transporters (ABCB) (10, 22). The induction of hydrolases, and perhaps other
enzymes, by rifampin has been suggested to increase the generation of reactive
metabolites from isoniazid that are hepatotoxic, thus helping to explain the interactive
toxicity of isoniazid and rifampin (23). Another suggested mechanism contributing to
such interactive toxicity is PXR-mediated effects on heme biosynthesis leading to an
accumulation of hepatotoxic protoporphyrin IX (24). In a study involving patients who
received both antiretroviral agents and antituberculosis drugs, a significant association
was found between drug-induced hepatic dysfunction and an NAT-2 slow-acetylator
genotype, as well as the ABCB1 3435TT genotype (25). In another study, the PXR TT
genotype was found to be associated with an increased risk of antituberculosis
drug-induced liver injury (26).
Pyrazinamide is increasingly recognized as an antituberculosis drug that can
result in significant hepatotoxicity in clinical settings. In a case-control study, the
adjusted odds ratio of hepatotoxicity for continuation-phase regimens incorporat-
ing pyrazinamide, isoniazid, and/or rifampin, relative to standard regimens, was
shown to be about three (27). In a rat model, changes in the activities of major
antioxidant enzymes and nonenzymatic antioxidants, principally including super-
oxide dismutase (SOD), antioxidant capacity, GSH, and malondialdehyde, were
found to be significantly associated with pyrazinamide-induced injury, alluding to
the role of oxidative stress in the pathogenesis of the drug-induced hepatotoxicity
(28). In a subsequent experiment using the same model, the expression of PPAR␣,
alongside the target genes downstream, was shown to be downregulated in the
face of pyrazinamide-induced hepatotoxicity, with a negative correlation of the
expression level with the severity of liver injury (29). The liver injury was amelio-
rated by fenofibrate, a PPAR␣ agonist. These data further support the role of
oxidative stress in pyrazinamide-induced hepatotoxicity.

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RISK FACTORS OF ANTITUBERCULOSIS DRUG-INDUCED HEPATOTOXICITY AND

THEIR ASSOCIATION WITH OXIDATIVE STRESS
Aside from the slow-acetylator status and the genetic polymorphisms pertaining to
CYP2E1 and GST mentioned, predisposing one to hepatotoxicity induced by antituber-
culosis drugs, the other clinical conditions that increase the risk of such drug-associated
toxicity mainly include old age, malnutrition, alcoholism, chronic viral hepatitis B and C
infections, and HIV infections, as well as preexisting liver diseases (8–10). It is imperative
to briefly review these comorbid conditions, in the context of oxidative stress (or more
broadly redox imbalance), to enable a better understanding of the pertinent drug-
disease interaction.
Aging and oxidative stress. Oxidative stress and beyond is now strongly believed

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to contribute to the biophysiology of aging and the pathogenesis of a number of
degenerative diseases involving principally the cardiovascular, neurological, and der-
matological systems (30, 31). In old age, immunological senescence often develops, and
there is likely an interaction between immunological dysfunction and oxidative stress
(and redox homeostasis and mitochondrial dysfunction) in elderly subjects (32). The
association between tuberculosis and old age has been reported in many countries and
geographical regions, largely related to a high prevalence of latent tuberculosis infec-
tion, with increased risk of progression/reactivation to disease, especially in the pres-
ence of comorbid conditions, such as smoking, alcoholism, and diabetes mellitus (33,
34). A possible underlying mechanism is the propensity for the formation of dormant/
semidormant Mycobacterium tuberculosis persisters in the face of oxidative stress (34).
As discussed, oxidative stress plays an important role in the pathogenesis of hepato-
toxicity induced by antituberculosis drugs. Recent clinical evidence also points to an
increased risk of antituberculosis drug-induced adverse reactions (inclusive of hepato-
toxicity) in older patients (35), especially in the presence of diabetes mellitus (36, 37).
In older people with type 2 diabetes mellitus, complications of the metabolic disease
resulting in organ dysfunction often have oxidative stress likely contributing to their
pathogenesis (34, 37). The results from animal experiments have helped substantiate
the hypothesis. For example, alloxan-induced diabetes has been shown to cause
morphological and ultrastructural changes in the rat liver that resemble the natural
history of chronic fatty liver disease in humans (38). Other experiments have similarly
demonstrated cardiovasculopathy, neuropathy, and nephropathy associated with oxi-
dative stress in the animal models (39–41). Thus, due to the shared pathogenetic basis
for organ injury in diabetic patients who receive antituberculosis therapy concomi-
tantly, it is biologically plausible that the diabetic complications can aggravate the
aftermath of antituberculosis drug-induced toxicities (37). Indeed, more research re-
garding the metabolic control of diabetes mellitus and the risk of toxicities induced by
antituberculosis therapy appears to be warranted.
Malnutrition and oxidative stress. In malnutrition, oxidative stress is heightened,
and impoverished nutritional status is conspicuously associated with immune dysfunc-
tion (42, 43). Hepatic steatosis has also been found in the malnourished animals and
humans, with a likely link to oxidative stress and mitochondrial dysfunction (44, 45). It
is conceivable that malnutrition would especially merit attention in the elderly popu-
lation with tuberculosis. Relevant knowledge hopefully can further accumulate.
Alcoholic liver disease and oxidative stress. The main pathway of conversion of
ethanol to acetaldehyde, together with the reduction of NAD to NADH, using the
alcohol dehydrogenase system takes place in the liver (2). Acetaldehyde is further
oxidized to acetate by aldehyde dehydrogenase. The other important pathway, also in
the liver, involves the inducible microsomal ethanol-oxidizing system, which entails
CYP2E1, an NADPH-requiring enzyme (2). During ethanol metabolism in these two
systems, NADH or NADP⫹ is produced, together with an increase in ROS generation,
and thus oxidative stress. DNA damage, lipid peroxidation, and formation of protein
adducts then result, along with mitochondrial dysfunction (2). Pathologically, steatosis,
fibrosis, cirrhosis, and even malignant changes are manifested in the hepatocytes of

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patients with clinical liver disease. Studies of enzymatic and nonenzymatic systems in
addressing the pro-oxidant and antioxidant status in animal models and subjects with
chronic alcoholism have been performed, however, with somewhat disparate results
(2). As in diabetes mellitus, the shared pathogenetic basis of oxidative stress for organ
injury highlights the possible mechanism underlying disease-drug interaction when
patients with alcoholic liver disease receive antituberculosis treatment.
Chronic viral hepatitis and oxidative stress. The relative risk of developing
antituberculosis drug-induced hepatotoxicity among patients with chronic viral hepa-
titis is about 3- to 5-fold that of the general population (8, 10). Studies have also shown
that the severity of hepatotoxicity was related to the viral load at the time of initiating
antituberculosis therapy (46, 47). In the face of chronic viral hepatitis, the host immune

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responses are largely responsible for the generation of ROS and RNS, as well as
mitochondrial dysfunction. It has also been shown that hepatitis C infection is associ-
ated with a greater production of ROS than other hepatitis viruses (48, 49). The level of
ROS was found to correlate with the likelihood of developing chronic hepatic disease,
namely, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. ROS has also been
found to affect viral genome translation and induce viral genome heterogeneity. A
number of core viral proteins of hepatitis C virus are associated with oxidative stress.
Hepatitis C virus also affects enzymes, some of which pertain to antioxidant pathways.
The availability of much information notwithstanding, huge gaps in the knowledge still
exist regarding ROS scenarios in hepatitis C infection. Interestingly, steatosis is one
conspicuous histopathological feature in chronic liver disease due to hepatitis C
infection. It appears that both host and virus factors contribute to the development of
this liver pathology, which is probably caused by ROS/RNS-mediated disturbance in
lipid metabolism. Furthermore, there appears a link between chronic hepatitis C
infection and insulin resistance and diabetes mellitus (50, 51). Taken together, the
information underscores extremely important awareness regarding the enhanced pre-
disposition to hepatotoxicity incurred by chronic hepatitis C disease and antitubercu-
losis therapy. In chronic hepatitis B infection, there is also some evidence for the
occurrence of oxidative stress (52). As in chronic hepatitis C infection, sometimes the
studies regarding antioxidant status have yielded rather conflicting results in patients
with chronic hepatitis B infection (49, 52). This notwithstanding, great vigilance has to
be exercised regarding the impact of an ROS-based pathogenetic mechanism in
causing antituberculosis drug-associated hepatotoxicity in patients with chronic hep-
atitis B infection.
HIV infection and oxidative stress. The relative risk of antituberculosis drug-
induced hepatotoxicity in HIV-infected subjects is about 4, but it rises to 14 when
concomitant hepatitis C infection is present (53). In HIV-associated tuberculosis, the
increased risk of hepatotoxicity could result from the shared mechanisms of liver injury
due to antituberculosis drugs and host factors, as related to oxidative stress and
beyond (54). To complicate the scenario further, there have been reports regarding the
perturbation of redox homeostasis during antiretroviral therapy with nucleoside and
nonnucleoside reverse transcriptase inhibitors, as well as viral protease inhibitors (55,
56). Nevirapine is the most hepatotoxic nonnucleoside reverse transcriptase inhibitor,
and the majority of nucleoside reverse transcriptase inhibitors, such as didanosine and
stavudine, are also potentially hepatotoxic (9). Highly active antiretroviral therapy, with
inclusion of HIV protease inhibitors, can result in hepatotoxicity in 18 to 27% of
recipients in some studies (9, 10).

PHARMACOGENOMICS OF DRUG-INDUCED LIVER INJURY

In parallel with the improvement of technologies in genome analysis, novel con-
cepts in the mechanisms of drug-induced hepatotoxicity have underlined nonspecific
downstream events following drug-specific upstream injury and the complex interac-
tions between environmental and genetic risk factors. Attention to genes beyond the
context of drug disposition and metabolism appears imperative, especially in relation
to human leukocyte antigen (HLA) system variability, immune response, and oxidative

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TABLE 2 Examples of genes putatively associated with isoniazid-induced hepatotoxicitya

Gene Genetic polymorphisms Possible results
NAT2 NAT2 *2, *5, *6, *7 Risk of hepatotoxicity
CYP2E1 CYP2E1*1A,*5,*6 Risk of hepatotoxicity
GSTb GSTM1, GSTT1 null homozygous Risk of hepatotoxicity
UGT1A TA insertion in gene promoter Risk of hyperbilirubinemia and hepatotoxicity
HLA HLA-DQ Risk of hepatotoxicity
NOS NOS2A (inducible isoform) Risk of hepatotoxicity
BACHb BACH1 CC genotype at rs11080344 Risk of hepatotoxicity
MAFKb Homozygous mutant genotype at rs4720833 Risk of hepatotoxicity
MnSODb Homozygous/heterozygous mutant C allele (T/C or C/C) Risk of hepatotoxicity
ABCB11c T¡C V444A Risk of hyperbilirubinemia and hepatotoxicity?
ABCB4c Various transversions
ABCC2c Various transversions

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SLCO1B1c T¡C V174A Risk of hepatotoxicity?
aABCB4, ATP binding cassette superfamily B member 4; ABCB11, ATP binding cassette superfamily B member 11; ABCC2, ATP binding cassette superfamily C member
2; BACH, BTB and CNC homolog basic leucine zipper transcription factor; HLA, human leukocyte antigen; MAFK, Maf basic leucine zipper protein; MnSOD, manganese
superoxide dismutase; NOS, nitric oxide synthase; SLCO1B1, solute carrier organic anion transporter family member 1B1; UGT, UDP glucuronosyltransferase.
bAssociated with antioxidative defense.

cMay contribute to interactive hepatotoxicity of rifampin and isoniazid.

stress (57, 58). In recent years, the pharmacogenomics knowledge base has been
accumulating (57–60). Table 2 depicts some important genes, apart from NAT2, CYP2E1,
and GST, which may be associated with isoniazid-induced hepatotoxicity. For truly
idiosyncratic drug-induced liver injury, it might be difficult to estimate the population-
attributable risk and clinically relevant absolute risk regarding these genetic polymor-
phisms. However, regarding some populations with risk factors for antituberculosis
drug-induced hepatotoxicity, further fathoming appears justified. In this connection, it
also appears that more research is warranted regarding the possible interaction be-
tween genetic polymorphisms associated with drug metabolism and oxidative stress, in
the generation of drug-induced liver injury. As an example, genetic variation of SOD2
has recently been found to be associated with alcoholic cirrhosis (61), and genetic
polymorphisms of SOD2 and cytochrome CYP 2E1 have been found to be associated
with nonalcoholic steatohepatitis (62).

EPILOGUE
Oxidative stress, nitrosative stress, and overall redox imbalance likely contribute to
antituberculosis drug-induced hepatotoxicity, especially in demographic subpopula-
tion(s) or patient groups with specific comorbidities (34–36). Our current ability to
predict, prevent, or treat hepatotoxicity remains limited. The need for clinical vigilance
and programmatic management of tuberculosis cannot be overemphasized. This is
imperative largely for preventing the development of hepatotoxicity or rendering
proactive management when hepatotoxicity is diagnosed at the earliest opportunity to
forestall its worsening in severity. One frequent measure is drug regimen modification
(8–10). Attention to nutritional status is of particular importance in elderly people with
both latent tuberculosis infection and tuberculosis. Optimal metabolic control in
diabetes-associated tuberculosis can have a favorable impact on the outcomes of both
diseases, including antituberculosis drug-induced toxicities (34).
The use of antioxidants may have an adjunctive role, but the benefit of such therapy
requires further delineation (2, 10), perhaps implying the complex nature of perturba-
tion in redox homeostasis, as well as the great likelihood of concomitant mitochondrial
dysfunction (63–65). At present, for overall drug-induced hepatotoxicity, animal exper-
iments are abundant, but there are only limited clinical studies (2). Coadministration of
N-acetylcysteine was found to be protective against liver injury in animals treated with
hepatotoxic doses of isoniazid and rifampin (66). In an open-label trial involving
patients ⬎60 years old, N-acetylcysteine appeared to protect against liver chemistry
abnormalities during antituberculosis treatment (67). The methodology of this trial,
however, precluded unequivocal conclusions to guide the management of antituber-
culosis drug-induced hepatotoxicity. In many animal experiments, herbal plants were

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investigated for hepatoprotection. The use of herbal products, albeit occasionally

encouraging, requires proper evaluation in well-designed clinical trials (2, 68). An
endeavor that systematically reviewed the ingredients and evaluation in studies in-
volving drugs and plants for hepatoprotection during antituberculosis therapy has not
yielded sufficient evidence to support advocating such an approach (69).
In chronic viral hepatitis, the use of antioxidants has not been shown to be definitely
beneficial for the liver disease per se and indeed might prove to be the contrary in some
patients. It has been suggested that patients with chronic hepatitis B infection might
harvest therapeutic results with antioxidants, only if appropriate selection of candidates
is undergone; thus, more pertinent research is mandatory (52). On the other hand, since
the severity of hepatotoxicity has been shown to be related to the viral loads of chronic
hepatitis B and hepatitis C infection at the time of commencement of antituberculosis

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therapy, antiviral therapy would likely have greater value. The possibility of a reduction
of risk of antituberculosis drug-induced hepatotoxicity in these patients with antiviral
therapy also appears promising from the results of preliminary studies, and evaluations
in controlled clinical trials are ongoing (70, 71). Whether the beneficial effect of such
viral load modulation is linked with a change in oxidative stress merits further research.
In the coming decade, the pathogenesis of hepatotoxicity during antituberculosis
therapy should be further unraveled, using better experimental models and human
tissue samples (10). More robust clinical studies should also be performed, including
those for evaluating the role of pharmacogenetics in the clinical management of
antituberculosis drug-induced hepatotoxicity (58, 72, 73).

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aac.asm.org 10
 ERRATUM

crossm

Erratum for Yew et al., “Oxidative Stress and First-Line

Antituberculosis Drug-Induced Hepatotoxicity”
Wing Wai Yew,a Kwok Chiu Chang,b Denise P. Chana

a
Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China
b Tuberculosis and Chest Service, Department of Health, Hong Kong, China

Volume 62, no. 8, e02637-17, 2018, https://doi.org/10.1128/AAC.02637-17. In the

abstract, the fifth and eighth sentences should read as follows:
Importantly, these comorbid conditions are associated with oxidative stress.
More translational research to unravel the pathogenesis, inclusive of the underlying
molecular basis, regarding antituberculosis drug-induced hepatotoxicity is needed, and
so is clinical research pertaining to the advances in therapy with antioxidants and drugs
related to antioxidants, especially those for management of mitochondrial dysfunction.

Citation Yew WW, Chang KC, Chan DP. 2018.

Erratum for Yew et al., “Oxidative stress and
first-line antituberculosis drug-induced
hepatotoxicity.” Antimicrob Agents Chemother
62:e01633-18. https://doi.org/10.1128/AAC
.01633-18.
Copyright © 2018 American Society for
Microbiology. All Rights Reserved.
Address correspondence to Denise P. Chan,
denisechan@cuhk.edu.hk.

October 2018 Volume 62 Issue 10 e01633-18 Antimicrobial Agents and Chemotherapy aac.asm.org 1