Molecular mechanisms underlying chemical liver injury

Abstract

The liver is necessary for survival. Its strategic localisation, blood flow and prominent role in the metabolism of xenobiotics render this organ particularly susceptible to injury by chemicals to which we are ubiquitously exposed. The pathogenesis of most chemical-induced liver injuries is initiated by the metabolic conversion of chemicals into reactive intermediate species, such as electrophilic compounds or free radicals, which can potentially alter the structure and function of cellular macromolecules. Many reactive intermediate species can produce oxidative stress, which can be equally detrimental to the cell. When protective defences are overwhelmed by excess toxicant insult, the effects of reactive intermediate species lead to deregulation of cell signalling pathways and dysfunction of biomolecules, leading to failure of target organelles and eventual cell death. A myriad of genetic factors determine the susceptibility of specific individuals to chemical-induced liver injury. Environmental factors, lifestyle choices and pre-existing pathological conditions also have roles in the pathogenesis of chemical liver injury. Research aimed at elucidating the molecular mechanism of the pathogenesis of chemical-induced liver diseases is fundamental for preventing or devising new modalities of treatment for liver injury by chemicals.

Figure 1. Generation of excess reactive chemical species leads to molecular damage in hepatocytes

Reactive species (pink boxes) are generated during biotransformation of toxicophores, which can then be detoxified by drug-metabolising enzymes and antioxidant systems (green boxes). Excess reactive chemical species react with biomolecules to form molecular adducts, peroxides or broken molecular fragments (purple box), resulting in dysfunction or change in the structure of biomolecules. Green arrows indicate detoxification pathways; red arrows show toxification pathways. CAT, catalase; GSH, glutathione; GPX, glutathione peroxidase; GST, glutathione S-transferase; NOS, nitric oxide synthase; NQO1, NAD(P)H quinone oxidoreductase 1; Prx, peroxiredoxin; SOD, superoxide dismutase; SULT, sulfotransferase; UGT, glucuronosyltransferase. Parts of this figure are adapted from portions of figures from Refs , .

Figure 2. Liver cell death occurs when the integrity of cellular organelles is impaired by oxidative stress and damage to biomolecules

Damage to biomolecules and oxidative stress can be reversed or tolerated by activation of compensatory responses. Excessive damage or modification of biomolecules by oxidative stress can overwhelm the capacity of repair and adaptive processes, leading to uncorrected changes to critical organelles, among which mitochondria is the most important. This can lead to activation of immune responses, which could further aggravate cellular damage. The interplay between xenobiotic-induced molecular changes, organelle dysfunction and activation of immunity results in cell death and liver injury. Cellular ATP availability is an important determinant of the type of cell death that occurs. Programmed cell death or apoptosis requires ATP, whereas oncotic death (necrosis) predominates when ATP stores are depleted. However, massive apoptosis also leads to apoptotic necrosis. Green boxes indicate normal homeostasis; boxes of other colours show events leading to liver cell injury. Green arrows indicate pathways leading to cell recovery; red arrows show pathways leading to cell damage or death.

Figure 3. The pathogenesis of chemical liver injury is controlled by genetic, environmental, patho-physiological and dietary factors

Other factors such as gender, race, age and lifestyle choices can be risk factors for certain forms of chemical liver injury. The interplay between these factors controls gene transcription and cell signalling events, leading to a myriad of interconnected outcomes such as imbalances between detoxification and toxification metabolic pathways, impaired organelle function, compromised ability to repair molecular damage and alterations in overall cellular homeostasis. With prominent shifts in normal cellular homeostasis, the ability of compensatory and adaptive responses to correct the detrimental effects of toxicants can be hampered. Similarly, repair mechanisms can be overwhelmed and incapable of correcting the cellular chemical injury. Green arrows indicate pathways leading to cell recovery; red arrows show pathways to cell damage or death; black arrows indicate pathways that contribute to chemical-induced liver injury.