The role of different cytochrome P450 isoforms in in vitro chloroform metabolism

摘要: The two CHCl3 activation pathways have been studied in incubations at different oxygenation conditions with hepatic microsomes from control Sprague Dawley (SD) rats or SD treated cytochrome P450 inducers (acetone, phenobarbital, pyrazole, dexamethasone, and beta-naphthoflavone). present results provide direct evidence that concentration is critical determining the role of isoforms (CYP) related effects metabolic inducers. At 0.1 mM concentration, only major contribution to its oxidative biotransformation liver untreated was due CYP2E1, as shown by inhibition 4-methylpyrazole anti-CYP2E1 antibodies. Moreover, animal treatments acetone pyrazole increased production adducts phosgene microsomal phospholipid about 10-15 times. 5 chloroform, rat microsomes, CYP2B1/2 participant responsible for chloroform activation, while CYP2E1 CYP2C11 were also significantly involved. Consistently, this effect phenobarbital (CYP2B1/2 inducer) maximal, producing very high levels adducts. reductive pathway expressed not any used. it inhibited metyrapone anti Therefore, may be concluded that, range concentrations tested, those CYPs involved bioactivation do participate reduction. Chloroform metabolism PB-microsomes could achieve absolute rates, much higher than C-microsomes; contrast, rates AC- PYR-microsomes remained within activity observable C-microsomes concentration. can argued CYP2B1/2-mediated induction basis PB potentiating hepatotoxicity. processes other CYP2E1-mediated more relevant ketones potentiation chloroform-induced acute toxicity.