Mechanisms of Chemically Induced Hepatotoxicity

The most direct mechanism of hepatotoxicity is through specific interaction of a chemical with a key cellular component and consequential modulation of its function. More common mechanisms, however, involve secondary effects of toxicant interaction. These include depletion of cellular molecules, such as ATP and GSH free radical and oxidant damage, in particular to membrane lipids covalent binding of reactive metabolites to critical cellular molecules and collapse of regulatory ion gradients. The following discussion will highlight how these cellular and molecular mechanisms contribute to specific types of chemically induced hepatic lesions. 

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GdClj has been used to study the mechanisms of chemical-induced hepatotoxicity (Badger et al. 1997, Sauer et al. 1997). Since lanthanides have an affinity for reticuloendothelial cells, GdClj injection selectively destroys Kupffer cells (the resident macrophage cell in the liver), and this results in protection of the liver from a number of toxicants hence, a role is suggested for these cells in chemical-mediated hepatotoxicity. The role of Kupffer cells in hepatotoxicity was implicated for those compounds required to undergo biotransformation before eliciting their toxicity (e.g., 1,2-dichlorobenzene and carbon tetrachloride), as well as those chemicals which do not (e.g., cadmium chloride). 

The widespread use of isoniazid prophylaxis for tuberculosis has focused attention on the liver injury caused by this drug. About 20% of patients treated with isoniazid will show elevated blood concentrations of liver enzymes and bilirubin that subside as treatment is continued (25). However/ clinical hepatitis develops in some patientS/ and these reactions can prove fatal. Current understanding of the mechanism of isoniazid-induced hepatotoxicity is based on the metabolic pathways shown in Figure 16.6 (26/ 27). It has been demonstrated in an animal model that hepatotoxicity is correlated with plasma concentrations of hydrazine but not of acetylhydrazine or isoniazid (28)/ and that pretreatment with an amidase inhibitor can prevent toxicity (27). However/ it is postulated that hydrazine is further metabolized to a chemically reactive he pa to toxin by the cytochrome P450 system/ and in vitro studies with hepatocytes have implicated CYP2E1 as the cytochrome P450 isoform responsible for cytotoxic metabolite formation (29). 

MEHENDALE, H.M., ROTH, R.A., GANDOLFI, A.J., KLAUNIG, J.E., LEMASTERS, J.J. and CURTIS, L.R. (1994) Novel mechanisms in chemically induced hepatotoxicity. FASEBJ., 8, 1285. NELSON, S.D. (1995) Mechanisms of the formation and disposition of reactive intermediates that can cause acute liver injury. Drug Metab. Rev., 27, 147. 

Gibson JD, Pumford NR, Samokyszyn VM, Hinson JA (1996) Mechanism of acetaminophen-induced hepatotoxicity covalent binding versus oxidative stress. Chem Res Toxicol 9 580-585 Gillette JR, Nelson SD, Mulder GJ, Jollow DJ, Mitchell JR, Pohl LR, Hinson JA (1981) Formation of chemically reactive metabolites of phenacetin and acetaminopheiL Adv Exp Med Biol 136 (Pt B) 931-950... 

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