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In vitro studies on the metabolic activation of the pulmonary toxin, 4-ipomeanol, by rat lung and liver microsomes.
J Pharmacol Exp Ther. 1978 Dec; 207(3):677-86.JP

Abstract

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.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

32381

Citation

Boyd, M R., et al. "In Vitro Studies On the Metabolic Activation of the Pulmonary Toxin, 4-ipomeanol, By Rat Lung and Liver Microsomes." The Journal of Pharmacology and Experimental Therapeutics, vol. 207, no. 3, 1978, pp. 677-86.
Boyd MR, Burka LT, Wilson BJ, et al. In vitro studies on the metabolic activation of the pulmonary toxin, 4-ipomeanol, by rat lung and liver microsomes. J Pharmacol Exp Ther. 1978;207(3):677-86.
Boyd, M. R., Burka, L. T., Wilson, B. J., & Sasame, H. A. (1978). In vitro studies on the metabolic activation of the pulmonary toxin, 4-ipomeanol, by rat lung and liver microsomes. The Journal of Pharmacology and Experimental Therapeutics, 207(3), 677-86.
Boyd MR, et al. In Vitro Studies On the Metabolic Activation of the Pulmonary Toxin, 4-ipomeanol, By Rat Lung and Liver Microsomes. J Pharmacol Exp Ther. 1978;207(3):677-86. PubMed PMID: 32381.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro studies on the metabolic activation of the pulmonary toxin, 4-ipomeanol, by rat lung and liver microsomes. AU - Boyd,M R, AU - Burka,L T, AU - Wilson,B J, AU - Sasame,H A, PY - 1978/12/1/pubmed PY - 1978/12/1/medline PY - 1978/12/1/entrez SP - 677 EP - 86 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 207 IS - 3 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/32381/In_vitro_studies_on_the_metabolic_activation_of_the_pulmonary_toxin_4_ipomeanol_by_rat_lung_and_liver_microsomes_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=32381 DB - PRIME DP - Unbound Medicine ER -