Drug-induced hepatotoxicity is one of the leading cause of acute liver failure. It is generally considered as the primary reason that therapeutic drugs are eliminated from the commercial market. Multiple mechanisms can lead to drug hepatotoxicity.

The aim of drug metabolism is to enhance excretion of a less polar drug through the development of more polar metabolites. The resultant water soluble compound can be excreted from the body by the kidneys. In majority drugs, Phase I metabolism occurs via oxidation, reduction or hydrolysis by CYP450 enzymes that produces the polar metabolites. These are then made water soluble and available for excretion by Phase II metabolism through glucuronidation or sulphation. These processes of hepatic drug-metabolizing enzymes are also controlled by expression of genes correlated with these enzymes along with modifications in blood flow to the liver in normal and pathogenic states.

In case of hepatotoxicity, it can be induced by a drug or its metabolite directly by gaining access to proximally located vulnerable hepatocytes. The most common example of drug causing metabolism via this pathway is acetaminophen. Direct hepatotoxicity of acetaminophen is dose-related that is subsequent to either one large single dose or a large cumulative dose of the drug. The final pathway of hepatocyte toxicity is through binding of a toxic CYP2E1-derived metabolite, N-acetyl-p-benzoquinone imine (NAPQI), to subcellular organelles, which results in necrosis or apoptosis. Other drugs exhibiting direct hepatotoxicity from hepatocyte necrosis are bromfenac, or methotrexate while cocaine, phencyclidine or niacin can induce ischemic necrosis.

Metabolism plays a crucial role in the development of drug hepatotoxicity through the production of directly toxic or reactive metabolites, this effect is induced by three possible ways. The first way involves direct injury to the hepatocyte by altering important cellular functions. For example, metabolic activation of acetaminophen by CYP2E1 results in the development of the toxic metabolite NAPQI. This metabolite has a binding preference for intracellular organelles including the mitochondria and can trigger oxidant stress that plays an active role in the development of hepatocyte necrosis following the development of irreversible opening of mitochondrial membrane permeability transition pores. Similarly, to acetaminophen, NSAIDs like diclofenac also exhibit common mechanisms of hepatotoxicity through metabolic activation following by disruption of subcellular organelles.

The second way of the process of inducing directly toxic or reactive metabolites is through sensitization of the hepatocytes to cytokine-induced damage. Drug hepatotoxicity occurs when bacterial endotoxin, represented by LPS via TNF-α, in some cases, sensitizes the liver to injury resulting in moderate to severe necrosis. This method can be seen in drugs like chlorpromazine, diclofenac, amiodarone, ranitidine, trovafloxacin or halothane.

Additional role can be seen by reactive metabolites in the development of hepatotoxicity through irreversible covalent modification of native proteins by reactive metabolites formed during drug metabolism, also known as haptenization. These covalently altered proteins consequently increases immune recognition of these altered native proteins. This further triggers a cascade of cytokine driven immune reactions resulting in hepatotoxicity in a susceptible host.

Source: Njoku DB. Drug-induced hepatotoxicity: metabolic, genetic and immunological basis. Int J Mol Sci. 2014;15(4):6990-7003. Published 2014 Apr 22.