In vivo studies on the relationship between target organ alkylation and the pulmonary toxicity of a chemically reactive metabolite of 4-ipomeanol.
The pulmonary toxin, 4-ipomeanol, selectively alkylates the lungs of rats. Time-course and dose-response studies demonstrate a close correlation between the pulmonary alkylation and the lung toxicity of the compound. Without prior metabolism, 4-ipomeanol is not sufficiently reactive to alkylate tissue macromolecules. Inhibitors of the metabolism of 4-ipomeanol decrease both the pulmonary alkylation and toxicity of the compound, which suggests that the toxicity is due to an alkylating metabolite. Studies with inducers of the hepatic metabolism of 4-ipomeanol are consistent with the view that the toxic metabolite of the compound is actually formed in situ in the target tissue. Pretreatment of animals with diethylmaleate strikingly increases both the pulmonary alkylation and the lung toxicity of 4-ipomeanol. Studies of the tissue alkylating properties and toxicities of 4-ipomeanl analogs demonstrate the requirement for the furan moiety. The toxic metabolites of 4-ipomeanol appears to be a highly electrophilic reactant capable of binding irreversibly with nucleophilic macromolecular constituents of target tissue.
D000478:Alkylation; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005663:Furans / Q000378:metabolism / Q000633:toxicity; D007928:Lethal Dose 50; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008298:Maleates / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D011654:Pulmonary Edema / Q000139:chemically induced; D051381:Rats; D013347:Subcellular Fractions / Q000378:metabolism; D013729:Terpenes / Q000378:metabolism* / Q000633:toxicity; D013997:Time Factors; D014118:Toxins, Biological / Q000378:metabolism* / Q000633:toxicity
D005663:Furans; D008298:Maleates; D013729:Terpenes; D014118:Toxins, Biological; D006899:Mixed Function Oxygenases; C001470:4-ipomeanol