In vitro studies on the metabolic activation of the pulmonary toxin, 4-ipomeanol, by rat lung and liver microsomes.
Rat lung and liver microsomes mediated the biotransformation of the pulmonary toxin, 4-ipomeanol, to an alkylating metabolite. The enzyme-mediated microsomal alkylation required NADPH and oxygen and was strongly inhibited by carbon monoxide, which indicated the participation of a cytochrome P-450-dependent monooxygenase. Other studies with inhibitors including pyrazole, piperonyl butoxide, SKF-525A, and cobaltous chloride, and with the inducers phenobarbital and 3-methylcholanthrene, also were consistent with this view. The Km for the pulmonary microsomal alkylation pathway was more than 10-fold lower than for the hepatic microsomal pathway. There was no significant enzyme-mediated covalent binding of analogs of 4-ipomeanol lacking the furan moiety, suggesting that metabolic activation of the parent compound involves oxidation of the furan ring. Reduced glutathione prevented the microsomal alkylation by 4-ipomeanol, indicating the electrophilic nature of the alkylating metabolite.
D000478:Alkylation; D000818:Animals; D001711:Biotransformation; D004790:Enzyme Induction / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D005663:Furans / Q000138:chemical synthesis / Q000378:metabolism; D005978:Glutathione / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D009249:NADP / Q000378:metabolism; D051381:Rats; D013347:Subcellular Fractions / Q000201:enzymology; D013729:Terpenes / Q000138:chemical synthesis / Q000378:metabolism*; D014118:Toxins, Biological / Q000138:chemical synthesis / Q000378:metabolism*
D005663:Furans; D013729:Terpenes; D014118:Toxins, Biological; D009249:NADP; D006899:Mixed Function Oxygenases; D004851:Epoxide Hydrolases; D005978:Glutathione; C001470:4-ipomeanol