Oxidative Stress and First-Line Antituberculosis Drug-Induced Hepatotoxicity

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. Covering only first-line antituberculosis drugs, this review addresses whether and how oxidative stress and, more broadly, disturbance in redox homeostasis alongside mitochondrial 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. 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 hepatotoxicity (other than removing potentially hepatotoxic drugs) remains limited. 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. The role of pharmacogenetics in the clinical management of drug-induced hepatotoxicity also likely merits further evaluation.

Keywords: drugs; hepatotoxicity; tuberculosis.

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.

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.