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Characteristics of monooxygenase-mediated covalent binding of methoxychlor in human and rat liver microsomes.
Drug Metab Dispos. 1989 Sep-Oct; 17(5):487-94.DM

Abstract

The characteristics of the activation of methoxychlor by the hepatic microsomal monooxygenases and its covalent binding to microsomal proteins in human and untreated rat were compared. The Vmax of covalent binding is similar in both species, being 21 and 11 pmol/min/mg protein in human and rat, respectively. However, their Kmapp values show marked differences: 146 versus 5 microM for human and rat, respectively. These differences in Km values seem to reflect the affinities of the respective P-450s for methoxychlor in catalyzing the formation of the reactive intermediate (M*) and not the availability of acceptor binding sites. The observations that alternate substrates and inhibitors of P-450 monooxygenases inhibit covalent binding of methoxychlor to human liver microsomes, demonstrate that covalent binding is catalyzed by typical monooxygenases. Antioxidants/free radical scavengers, and sulfhydryl-containing compounds inhibit covalent binding in human liver microsomes, suggesting that the reactive intermediate is a free radical. A similar finding in phenobarbital (Pb)-treated rats (Bulger, Temple and Kupfer, Toxicol. Appl. Pharmacol. 68:367, 1983) indicates that the mechanism of covalent binding in the two species is similar. Of interest is the observation with human liver samples that, despite differences in age, sex, and, probably, in diet among individuals, their rates of covalent binding of methoxychlor were similar. By contrast, there is a much higher covalent binding in the mature male rat than in the mature female or immature male or female rat, suggesting that developmentally controlled male-specific P-450s contribute to covalent binding in the adult male.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

Worcester Foundation for Experimental Biology, Shrewsbury, MA 01545.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

2573491

Citation

Bulger, W H., and D Kupfer. "Characteristics of Monooxygenase-mediated Covalent Binding of Methoxychlor in Human and Rat Liver Microsomes." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 17, no. 5, 1989, pp. 487-94.
Bulger WH, Kupfer D. Characteristics of monooxygenase-mediated covalent binding of methoxychlor in human and rat liver microsomes. Drug Metab Dispos. 1989;17(5):487-94.
Bulger, W. H., & Kupfer, D. (1989). Characteristics of monooxygenase-mediated covalent binding of methoxychlor in human and rat liver microsomes. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 17(5), 487-94.
Bulger WH, Kupfer D. Characteristics of Monooxygenase-mediated Covalent Binding of Methoxychlor in Human and Rat Liver Microsomes. Drug Metab Dispos. 1989 Sep-Oct;17(5):487-94. PubMed PMID: 2573491.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characteristics of monooxygenase-mediated covalent binding of methoxychlor in human and rat liver microsomes. AU - Bulger,W H, AU - Kupfer,D, PY - 1989/9/1/pubmed PY - 1989/9/1/medline PY - 1989/9/1/entrez SP - 487 EP - 94 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 17 IS - 5 N2 - The characteristics of the activation of methoxychlor by the hepatic microsomal monooxygenases and its covalent binding to microsomal proteins in human and untreated rat were compared. The Vmax of covalent binding is similar in both species, being 21 and 11 pmol/min/mg protein in human and rat, respectively. However, their Kmapp values show marked differences: 146 versus 5 microM for human and rat, respectively. These differences in Km values seem to reflect the affinities of the respective P-450s for methoxychlor in catalyzing the formation of the reactive intermediate (M*) and not the availability of acceptor binding sites. The observations that alternate substrates and inhibitors of P-450 monooxygenases inhibit covalent binding of methoxychlor to human liver microsomes, demonstrate that covalent binding is catalyzed by typical monooxygenases. Antioxidants/free radical scavengers, and sulfhydryl-containing compounds inhibit covalent binding in human liver microsomes, suggesting that the reactive intermediate is a free radical. A similar finding in phenobarbital (Pb)-treated rats (Bulger, Temple and Kupfer, Toxicol. Appl. Pharmacol. 68:367, 1983) indicates that the mechanism of covalent binding in the two species is similar. Of interest is the observation with human liver samples that, despite differences in age, sex, and, probably, in diet among individuals, their rates of covalent binding of methoxychlor were similar. By contrast, there is a much higher covalent binding in the mature male rat than in the mature female or immature male or female rat, suggesting that developmentally controlled male-specific P-450s contribute to covalent binding in the adult male.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/2573491/Characteristics_of_monooxygenase_mediated_covalent_binding_of_methoxychlor_in_human_and_rat_liver_microsomes_ DB - PRIME DP - Unbound Medicine ER -