1,1,1-Trichloropropene-2,3-oxide: an alternate mechanism for its inhibition of cytochrome P-450.
Incubation of hepatic microsomes from phenobarbital treated rats, 1,1,1-trichloropropene-2,3-oxide (TCPO) (3 mM), EDTA (0.2 mM) and NADPH-gene-rating system in vitro decreased the levels of cytochrome P-450 by 40% and equivalently decreased microsomal heme. Appreciable losses of cytochrome P-450 were not observed [1] if metyrapone (2.3 mM) or CO:O2 (80:20; v/v) were included in incubation mixtures, [2] if the TCPO or NADPH-gene-rating system were omitted from reaction mixtures, or [3] if microsomes from untreated or beta-naphthoflavone treated rats were utilized. The time course for the TCPO mediated loss of hepatic microsomal cytochrome P-450 showed a time lag of 5 min, before the levels of cytochrome P-450 were significantly altered, followed by a 10-15 min period in which the levels of cytochrome P-450 rapidly decreased to a non-zero plateau level. The concentration of TCPO required for half maximal loss of cytochrome P-450 was ca. 0.5 mM. In the absence of cytochrome P-450 degradation, TCPO (2 mM) was an effective inhibitor of aminopyrine demethylase and benzpyrene-3-hydroxylase but not of p-nitroanisole demethylase or ethoxyresorufin deethylase. In contrast, the degradation of cytochrome P-450 by TCPO strikingly decreased ethoxyresorufin deethylase and to a lesser extent p-nitroanisole demethylase. A reaction mechanism is proposed for the TCPO mediated degradation of cytochrome P-450 in vitro.
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004987:Ethers / Q000494:pharmacology; D006418:Heme / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D014239:Trichloroepoxypropane / Q000494:pharmacology*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D004987:Ethers; D006843:Hydrocarbons, Chlorinated; D014239:Trichloroepoxypropane; D006418:Heme; D009249:NADP; D019324:beta-Naphthoflavone; D006899:Mixed Function Oxygenases; D010634:Phenobarbital