title: Metabolism of [3-14C]coumarin to polar and covalently bound products by hepatic microsomes from the rat, Syrian hamster, gerbil and humans.
abstract: The metabolism of 0.19 and 2.0 mM-[3-14C]coumarin to polar products and covalently bound metabolites has been studied with hepatic microsomes from the rat, Syrian hamster, Mongolian gerbil and humans. [3-14C]Coumarin was metabolized by liver microsomes from all species to a number of polar products and to metabolite(s) that became covalently bound to microsomal proteins. The polar products included 3-, 5- and 7-hydroxycoumarins, o-hydroxyphenylacetaldehyde and o-hydroxyphenylacetic acid. Coumarin 7-hydroxylation was observed in all species except the rat. With 0.19 mM-[3-14C]coumarin, 7-hydroxycoumarin was the major metabolite in human liver microsomes, whereas in the other species with 0.19 mM substrate and in all species with 2.0 mM substrate o-hydroxyphenylacetaldehyde was the major metabolite. Of the three animal species studied the gerbil most resembled humans as this species also had a high coumarin 7-hydroxylase activity. The administration of Aroclor 1254 to the rat and Syrian hamster induced both microsomal cytochrome P-450 content and [3-14C]coumarin metabolism. With liver microsomes from all species a good correlation between rates of [3-14C]coumarin metabolism and covalent binding was observed at both substrate concentrations. However, in view of the known species difference between the rat and Syrian hamster in coumarin-induced hepatotoxicity, the present data are not consistent with microsomal coumarin metabolite covalent binding being an indicator of potential liver damage.
authors.affiliation: BIBRA Toxicology International, Carshalton, Surrey, UK.
authors.forename: B G
authors.initials: BG
authors.lastname: Lake
authors.forename: H
authors.initials: H
authors.lastname: Gaudin
authors.forename: R J
authors.initials: RJ
authors.lastname: Price
authors.forename: D G
authors.initials: DG
authors.lastname: Walters
mesh_terms: D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D002648:Child; D020111:Chlorodiphenyl (54% Chlorine); D003374:Coumarins / Q000378:metabolism*; D006224:Cricetinae; D005260:Female; D005849:Gerbillinae; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D010648:Phenylacetates / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
chemical_list: D001140:Aroclors; D003374:Coumarins; D010648:Phenylacetates; D020111:Chlorodiphenyl (54% Chlorine); C070647:2-hydroxyphenylacetaldehyde; C030123:coumarin; D000079:Acetaldehyde; C005756:2-hydroxyphenylacetic acid