Hepatotoxicity metabolic activation

Hinson, J.A. Reid, A.B. McCullough, S.S. James, L.P. (2004). Acetaminophen-induced hepatotoxicity role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metabolism Reviews, Vol.36, No. 3-4, (January 2004), pp. 805-822, ISSN 0360-2532. 

Lin G, Cui Y-Y, Liu X-Q and Wang Z-T (2002b), Species differences in the in vitro metabolic activation of the hepatotoxic pyrrolizidine alkaloids clivorine , Chem Res Toxicol, 15, 1421-1428. 

Park, B.K. et al. 2005. The role of metabolic activation in drug-induced hepatotoxicity. Annu. Rev. Pharmacol. Toxicol. 45 177. 

Letteron P, Degott C, Labbe G, et al. 1987. Methoxsalen decreases the metabolic activation and prevents the hepatotoxicity and nephrotoxicity of chloroform in mice. Toxicol Appl Pharmacol 91 266-273. 

Haloalkanes. Certain haloalkanes and haloalkane-containing mixtures have been demonstrated to potentiate carbon tetrachloride hepatotoxicity. Pretreatment of rats with trichloroethylene (TCE) enhanced carbon tetrachloride-induced hepatotoxicity, and a mixture of nontoxic doses of TCE and carbon tetrachloride elicited moderate to severe liver injury (Pessayre et al. 1982). The researchers believed that the interaction was mediated by TCE itself rather than its metabolites. TCE can also potentiate hepatic damage produced by low (10 ppm) concentrations of carbon tetrachloride in ethanol pretreated rats (Ikatsu and Nakajima 1992). Acetone was a more potent potentiator of carbon tetrachloride hepatotoxicity than was TCE, and acetone pretreatment also enhanced the hepatotoxic response of rats to a TCE-carbon tetrachloride mixture (Charbonneau et al. 1986). The potentiating action of acetone may involve not only increased metabolic activation of TCE and/or carbon tetrachloride, but also possible alteration of the integrity of organelle membranes. Carbon tetrachloride-induced liver necrosis and lipid peroxidation in the rat has been reported to be potentiated by 1,2- dichloroethane in an interaction that does not involve depletion of reduced liver glutathione, and that is prevented by vitamin E (Aragno et al. 1992). 

The converse is true of drugs requiring metabolic activation for toxicity. For example, paracetamol is less hepatotoxic to newborn than to adult mice, as less is metabolically activated in the neonate. This is due to the lower levels of cytochromes P-450 in neonatal liver (Fig. 5.30). Also involved in this is the hepatic level of glutathione, which is required for detoxication. Although levels of this tripeptide are reduced at birth, development is sufficiently in advance of cytochrome P-450 levels to ensure adequate detoxication (Fig. 5.30). The same effect has been observed with the hepatotoxin bromobenzene. (For further details of paracetamol and bromobenzene see chap. 7.) Similarly, carbon tetrachloride is not hepatotoxic in newborn rats as metabolic activation is required for this toxic effect, and the metabolic capability is low in the neonatal rat. 

Lee SH, Slattery JT (1997) Cytochrome P450 isozymes involved in lisofylline metabolism to pentoxifylline in human liver microsomes. Drug Metab Dispos 25 1354-1358 Li AP (1999) Cryopreserved human hepatocytes characterization of DME activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability and drug-drug interaction potential. Chem Biol Interact 121 17-35... 

Much is known about the biochemical toxicology of hepatotoxicants, yet much remains to be learned. Hepatotoxicity resulting in either cell necrosis, fibrosis, or fatty infiltration is known to be a widespread phenomenon, potentially of importance to human health. It is caused by numerous drugs and environmental agents, and its incidence is expected to increase as confounding viral liver disease becomes more prevalent. Much is known about mechanisms based upon comprehensive studies with a few prototypical chemicals—namely, CCb, ethanol and acetaminophen—which support a convergence of varied primary effects on the ultimate failure of mitochondrial function and Ca2+ homeostasis. The extensive metabolic activity of the liver exposes its cells to a continuous flux of prooxidants. The importance of metabolic activation for the production of reactive metabolites is well-... 

Kidneys have relatively low xenobiotic-metabolizing enzyme activities, and chemically induced nephrotoxicity has been assumed to be produced by toxic intermediates generated in the liver and transported to the kidney. If a single hepatic metabolite of chloroform produced both kidney and liver injury, species, strain, and sex differences in susceptibility to chloroform nephro- and hepatotoxicity should be similar. However, species, strain and sex differences in susceptibility to chloroform nephrotoxicity are not consistent with those of chloroform hepatotoxicity. In addition, several modulators of tissue xenobiotic-metabolizing activities alter... 

Mitchell JR, Nelson WL, Potter WZ, Sasame HA, Jollow DJ. Metabolic activation of furosemide to a chemically reactive, hepatotoxic metabolite. J Pharmacol Exp Ther 1976 199 41-52. 

Hepatocytes show a remarkable heterogeneity and functional specialization which systematically differs depending on the cell s position in the lobule (simplified overview Fig. Id). For hepatotoxicity it is particularly relevant that many cytochrome P450 enzymes (e.g., CYP2E1 and CYP3A4) are preferentially expressed in the center of the lobule. Since many hepatotoxic compounds such as paracetamol or CC14 are metabolically activated by these enzymes they lead to a specific pericentral pattern of hepatotoxicity. 

Baillie, T. A. Metabolic activation of valproic acid and drug-mediated hepatotoxicity. Role of the terminal olefin, 2-n-propyl-4-pente-noic acid. Chem. Res. Toxicol. 1988, 1, 195-199. 

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