Bioactivation cytochrome P450-mediated

In contrast to the A-monosubstituted carbamates, the A,A-disubstituted analogues (8.124 and 8.125, R = R R"NCO R = Me or Et R" = Me, Et, i-Pr, etc.) proved very stable at pH 7.4 in both buffer and plasma, with less than 5% degradation in 4 d. In fact, these compounds were potent inhibitors of plasma cholinesterase (EC 3.1.1.8), with K values ranging from 600 to 3 nM. Although these carbamates were stable in plasma, they underwent rapid bioactivation in liver, as demonstrated with mouse and rat liver microsomes. For example, the A,A-dimethylcarbamate (8.124, R = Me2NCO) was bioactivated in rat liver microsomes with t1/2 of ca. 30 min. Two routes of bioactivation were postulated, namely direct carboxylesterase-catalyzed hydrolysis, and cytochrome P450 mediated A-dealkylation to a more labile A-monosubstituted carbamate. 

H. Schroder, Cytochrome P450 Mediates Bioactivation of Organic Nitrates , J. Pharmacol. Exp. Ther. 1992, 262, 298-302. 

One type of isosteric substitution that should have tremendous potential in the design of safer commercial chemicals is replacement of hydrogen with fluorine. Since many bioactivation mechanisms of chemicals involve cytochrome P450-mediated hydrogen atom abstraction to yield toxic metabolites, it would seem plausible that replacement of such a hydrogen atom with fluorine would provide a safer isosteric analog, without affecting commercial efficacy. 

Li X, Kamenecka TM, Cameron MD (2010) Cytochrome P450-mediated bioactivation of the epidermal growth factor receptor inhibitor erlotinib to a reactive electrophile. Drug Metab Dispos 38 1238-1245... 

The effect of pipeline on the cytotoxicity and genotoxicity of aflatoxin Bi (AFBi) has been studied in rat hepatoma cells H4IIEC3/G-(H4IIE) using cellular growth and formation of micronuclei as endpoints [64]. Piperine markedly reduced the toxicity of aflatoxin. That is, AFBi-induced formation of micronuclei in a concentration-dependent manner probably by suppressing cytochromes P450 mediated bioactivation... 

Cytochrome P450 3A4-mediated bioactivation of raloxifene irreversible... 

The metabolism of 7V-nitrosodiethanolamine by a-hydroxylation, which is a cytochrome P450 (CYP)-mediated pathway, was not detected in liver preparations from uninduced male Fischer 344 rats (Farrelly et al., 1984,1987). The existence of a-hydroxylation was proved later, notably by the formation of glycol aldehyde in liver microsomes from rats pretreated with CYP2E1 inducers. The microsomal metabolism of N-nitrosodiethanolamine was slower by a-oxidation than by [3-oxidation (Loeppky, 1999). Bioactivation tests of jV-nitrosodiethanolamine in V79 Chinese hamster cells showed that cytotoxicity was observed only in cells transfected with human CYP2E1 but not in cells expressing CYP2B1 or in the controls (Janzowski et al., 1996 Loeppky, 1999). 

Weber, G.L., Steenwyk, R.C., Nelson, S.D. Pearson, PG. (1995) Identification of V-acetyl-cysteine conjugates of l,2-dibromo-3-chloropropane evidence for cytochrome P450 and glutathione mediated bioactivation pathways. Chem. Res. Toxicol., 8, 560-573... 

Chen Q, Ngui JS, Doss GA, et al. Cytochrome P450 3A4-mediated bioactivation of raloxifene irreversible enzyme inhibition and thiol adduct formation. Chem Res Toxicol 2002 15(7) 907-914. 

A major mechanism of chemical toxicity involves activation of chemicals by catalytic oxidation mediated by cytochrome P450 (cyt P450) enzymes in the liver.14 61 Lipophilic molecules bioactivated in this way often damage genetic material (i.e., DNA). They include styrene, benzo[a]pyrene, napthylamines, and many others.[7 11] Covalent DNA adducts of these activated molecules with DNA bases are important biomarkers of cancer risk in humans exposed to toxic molecules.[12 14]... 

Fourth, certain segments of the nephron have a capacity for metabolic bioactivation. For example, the proximal and distal tubules contain isozymes of the cytochrome P450 monooxygenase system that may mediate intrarenal bioactivation of several protoxicants. Additionally, prostaglandin synthetase activity in medullary and papillary interstitial cells may be involved in cooxidation of protoxicants, resulting in selective papillary injury. 

Dibenzofuran induces hepatic, skin, and lung cytochrome P450 lAl, 1A2, and aryl hydrocarbon hydroxylase in rats. Thus, toxicity results from aryl hydrocarbon receptor signal transduction pathway. Bioactivation of many polycyclic hydrocarbon carcinogens is mediated by these enzymes. 

Bui PH, Hsu EL, Hankinson O (2009) Fatty acid hydroperoxides support cytochrome P450 2S1-mediated bioactivation of benzo[a]pyrene-7,8-dihydrodiol. Mol Pharmacol 76 1044-1052... 

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