Biochemical and Cellular Mechanisms of Toxic Liver Injury

Neil Kaplowitz, M.D.

Disclosures

Semin Liver Dis. 2002;22(2) 

In This Article

Abstract and Introduction

The pathogenesis of drug- or toxin-induced liver injury usually involves the participation of toxic metabolites that either elicit an immune response or directly affect the biochemistry of the cell. The clinical appearance of hepatitis is then a consequence of cell death mediated by either the extrinsic immune system (e.g., cytotoxic T cells) or intracellular stress. Intracellular stress can lead to apoptotic or necrotic cell death, depending on the extent of mitochondrial involvement and the balance of factors that activate and inhibit the Bcl2 family of proteins and the caspases. Drug metabolites can undergo or promote a variety of chemical reactions, including covalent binding, depletion of reduced glutathione, or oxidative stress with consequent effects on proteins, lipids, and DNA. These chemical consequences can directly affect organelles such as mitochondria, cytoskeleton, endoplasmic reticulum, microtubules, or nucleus or indirectly influence these organelles through activation or inhibition of signaling kinases, transcription factors, and gene expression profiles. The outcome may be either triggering of the necrotic or apoptotic process or sensitization to the lethal action of cytokines of the immune system intrinsic to the liver.

Cell death is the crucial event leading to the clinical manifestations of drug-induced hepatotoxicity. In this review, the current concepts of cell death will be reviewed and placed in the context of drug hepatotoxicity. At the outset, it should be emphasized that the pathogenesis of clinical drug hepatitis reflects either an immune-mediated attack on the liver or a biochemical effect of toxic metabolites leading to a loss of cell viability.[1,2] Immune attack involves the participation of death receptors such as Fas or the porin-mediated introduction of granzyme to activate the death cascade distal to the death receptor.[3,4] The outcome is apoptosis of hepatocytes (or perhaps in some circumstances bile duct or endothelial cells).

The liver is usually the target of the immune system because of the production of drug metabolites that bind to proteins which are degraded to peptides presented on the cell surface with major histocompatibility complex class I. This leads to sensitization, which allows T cells to recognize the drug metabolite bound to liver protein (e.g., CYP) targeted to the hepatocyte surface.[5] In contrast, some drugs produce metabolites that cause cell death independent of the extrinsic immune system.[6] There are two ways in which this can happen: the reactive metabolites can disrupt the balance of factors that favor survival, leading to direct loss of viability, or they can modify this balance so as to render liver cells susceptible to the lethal effects of the intrinsic immune system, that is, cytokines such as tumor necrosis factor (TNF), produced by activation of resident inflammatory cells in the liver. The outcome can range from maintenance of viability to apoptosis or necrosis depending on the drug, the extent of exposure to reactive metabolites, and a variety of environmental and genetic factors that modulate drug metabolism, transport, defense, regeneration, cytokines, and prodeath and prosurvival genes.[2,4] Because most examples of drug-induced liver disease occur in a very small proportion of patients using any given agent, it is likely that the individual risk is determined by various combinations of the environmental and genetic variations in multiple factors.

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