Chemical mediated hepatotoxicity

Delaney, B. and Kaminski, N.E., Liver-immune interactions induced by hepatic regeneration similarities between partial hepatectomy and chemically mediated hepatotoxicity, in Experimental Immunotoxicology, Smialowicz, R J. and Holsapple, M.P., Eds., CRC Press, Boca Raton, 1996. 

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). 

Exposure to two or more chemical agents can result in altered expression of hepatotoxicity. However, qualitatively different interactions may be achieved, depending upon the relative timing of exposures. Simultaneous exposure to competing substrates of a specific CYP isozyme will often slow metabolism and can be protective against reactive metabolite-mediated hepatotoxicity. Alternately, pretreatment with one agent may induce metabolic enzymes that either protect against or potentiate... 

Several cases of hepatotoxicity associated with chaparral use have been described (see Section 16.5). The mechanism of chaparral-associated hepatotoxicity is unknown. It is not known if chaparral is an intrinsic hepatotoxin (i.e., toxic to everyone if the dose is sufficient) or an idiosyncratic hepatotoxin (i.e., toxic only to those who have certain genetically aberrant metabolic pathways or immune system defects). Proposed mechanisms of chaparral-associated hepatotoxicity include (1) inhibition of cyclooxygenase or cytochrome P-450, (2) an immune-mediated reaction, (3) formation of a toxic metabolite, (4) impairment of liver function by phytoestrogens found in chaparral, and (5) cholestatic mechanisms causing impairment of bile formation or excretion. There is likely overlap between the two categories and the various mechanisms. In addition, toxicity may be influenced by age, weight, nutritional status, exposure to other drugs and chemicals, cumulative dose, and preparation (i.e., tea, dried plant parts, etc.) (Sheikh et al., 1997). 

The formation of reactive intermediates resulting from the metabolism of carbon disulfide by the hepatic MFO system may be involved in the hepatoxicity of this chemical. Pretreatment of rats with phenobarbital, an inducer of MFO activity, can enhance carbon disulfide-induced hepatotoxicity (Bus 1985). Inhibition of the MFO system might potentially reduce carbon disulfide-mediated hepatoxicity. In support of this possibility, Bond and De Matteis (1969) reported that pretreatment of rats with SKF-525A, an inhibitor of cytochrome P-450-mediated metabolism, reduced the liver damage from carbon disulfide in phenobarbital-pretreated animals. 

Recently, McMurtry et al showed acetaminophen in Fischer rats becomes covalently bound to kidney as well as to liver (34). However, the chemically reactive metabolite in kidney a ears to be produced in the kidney rather than the liver since 3-methylcholanthrene pretreatment increased the covalent binding in the liver but not the kidney. Thus it seemed likely that the chemically reactive metabolite of acetaminophen formed in the liver has too short a half-life to leave the liver to any significant extent. Since N-hydroxyacetaminophen has a relatively long half-life vitro, the possibility that the hepatotoxicity of acetaminophen might be mediated mainly through this metabolite became questionable. 

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