Drug reactive metabolite-induced hepatotoxicity: a comprehensive review

Nowadays, drug-induced liver toxicity (DILT) is one of the main contributing factors to severe liver disease. In the United States (US) alone, DILT is the cause of more than 50% of instances of acute liver failure. Prescription or over-the-counter drugs, xenobiotics, and herbal and nutritional supplements can cause DILT and could produce anomalies in hepatic function tests. Some drugs induce hepatotoxicity directly, and others induce it indirectly (i. e. through their toxic or reactive metabolites). Currently, the United States Food and Drug Administration (US FDA) has issued black box warnings for about 1279 drugs due to their hepatotoxicity. When we analyzed their mechanism in inducing hepatotoxicity, we found nearly 18 drugs causing hepatotoxicity by their toxic metabolites. In this review, we attempted to highlight the well-known drugs that induce hepatotoxicity indirectly through their toxic metabolites including the enzymes involved in the formation of these metabolites. The Cytochrome P-450 (CYP), Hypoxanthine phosphoribosyltransferase 1, Alcohol oxidase, Uridine diphosphate (UDP)-glucuronosyltransferases, Xanthine dehydrogenase, Purine-nucleoside phosphorylase, Xanthine oxidase, Thiopurine S-methyltransferase, Inosine-5'-monophosphate dehydrogenase, and aldehyde dehydrogenase are involving in the formation of toxic metabolites. The metabolic reactions and enzymes discussed in this review help toxicologists, pharmacologists, and chemists to design and develop hepatotoxicity-free pharmaceutical products containing the inhibitors of these enzymes to reduce hepatotoxicity and improve human health.