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Key factors of susceptibility to anti-tuberculosis drug-induced hepatotoxicity

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Abstract

Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the leading adverse drug reactions during the course of tuberculosis treatment and poses a considerable challenge to clinicians and researchers. Previous studies have revealed the important contribution of drug metabolism and transporter enzymes to the complexity of ATDH. The emerging roles of immune response and oxidative stress resulting from reactive metabolite in the development of ATDH have also gained attention recently. Both non-genetic and genetic factors can have a significant impact on the susceptibility to ATDH, consequently altering the risk of hepatotoxicity in susceptible individuals. Non-genetic risk factors associated with ATDH include host factors, environment factors and drug-related factors. Genetic factors contributing to the susceptibility of ATDH involve genetic variations in bioactivation/toxification pathways via the cytochrome P450 enzymes (phase I), detoxification reactions by N-acetyl transferase 2, glutathione S-transferase and uridine diphosphate glucuronosyltransferase (phase II) and hepatic transport (phase III), together with immunological factors and antioxidant response. Better understanding of these factors may help to predict and prevent the occurrence of ATDH and develop more effective treatments. This review focuses on the mechanisms of ATDH and the key factors of susceptibility associated with drug metabolism, hepatic transport, immune response and oxidative stress.

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Abbreviations

ATDH:

Anti-tuberculosis drug-induced hepatotoxicity

ABC:

Adenosine triphosphate binding cassette

ADRs:

Adverse drug reactions

ALP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

AP:

Alkaline phosphatase

ARE:

Antioxidant response element

ASP:

Asparaginic acid

ATP:

Adenosine triphosphate

AST:

Aspartate transaminase

BACH1:

BTB and CNC homology 1

BCRP (ABCG2):

Breast cancer resistance protein

BMI:

Body mass index

CES:

Carboxylesterases

CI:

Confidence interval

CYP450:

Cytochrome P450

DIH:

Drug-induced hepatotoxicity

DILI:

Drug-induced liver injury

DMET:

Drug metabolism enzymes and transporters

EMB:

Ethambutol

GSH:

Glutathione

GST:

Glutathione S-transferase

GWAS:

Genome-wide association studies

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

HIV:

Human immunodeficiency virus

HLA:

Human leukocyte antigen

IL:

Interleukin

INH:

Isoniazid

Keap1:

Kelch-like ECH-associated protein 1

MAC:

Mid-arm circumference

MnSOD:

Manganese superoxide dismutase

MRP (ABCC):

Multidrug resistance associated proteins

NAT2:

N-acetyl transferase 2

Nrf2:

Nuclear factor erythroid 2-related factor 2

NTCP (SLC10A1):

Sodium taurocholate co-transporting polypeptides

OAT:

Organic anion transporter

OATP (SLCO):

Organic anion-transporting polypeptide

OR:

Odds ratio

P-gp (MDR1, ABCB1):

P-glycoprotein

PZA:

Pyrazinamide

RMP:

Rifampicin

ROS:

Reactive oxygen species

SLC:

Solute carrier

SM:

Streptomycin

SNP:

Single-nucleotide polymorphisms

TB:

Tuberculosis

TNF-α:

Tumor necrosis factor-α

UGT:

Uridine diphosphate glucuronosyltransferase

ULN:

Upper limit of normal

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Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, 38 Xueyuan Road, Haidian District, Beijing, 100191, People’s Republic of China

    Ru Chen, Jing Wang & Siyan Zhan

  2. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada

    Yuan Zhang

  3. Department of Epidemiology and Biostatistics, Nanjing Medical University, Nanjing, People’s Republic of China

    Shaowen Tang

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  1. Ru Chen
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  2. Jing Wang
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  3. Yuan Zhang
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  4. Shaowen Tang
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  5. Siyan Zhan
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Correspondence to Siyan Zhan.

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Chen, R., Wang, J., Zhang, Y. et al. Key factors of susceptibility to anti-tuberculosis drug-induced hepatotoxicity. Arch Toxicol 89, 883–897 (2015). https://doi.org/10.1007/s00204-015-1473-1

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