Metabolism of coumarin by rat, gerbil and human liver microsomes.
1. o-Hydroxyphenylacetaldehyde was the major metabolite of coumarin (1 mM) in rat, gerbil and human liver microsomes. 2. Treatment of rats with phenobarbitone (PB) or beta-naphthoflavone increased the o-hydroxyphenylacetaldehyde formed. 3-Hydroxycoumarin was the other main metabolite produced by rat liver microsomes. 3. Liver microsomal metabolism of coumarin in gerbil was extensive with 3-, 5-, 6-, 7- and 8-hydroxycoumarins, and 3,7- and 6,7-dihydroxycoumarins produced, in addition to o-hydroxyphenylacetaldehyde. The profile of the hydroxy metabolites was altered by in vivo treatment of gerbils with cytochrome P-450 inducers, but there was no increase of coumarin metabolism. 4. Coumarin was metabolized by human liver microsomes to o-hydroxyphenylacetaldehyde, 7-hydroxycoumarin, 3-hydroxycoumarin, and trace amounts of 5-, 6- and 8-hydroxycoumarins. 5. At low substrate concentrations (0-10 microM) hepatic microsomal metabolism of coumarin in gerbil resembled that in man, with 7-hydroxycoumarin being a major metabolite. However, the production of o-hydroxyphenylacetaldehyde was greater in gerbil than human liver microsomes. 6. At higher substrate concentrations (1 mM) metabolism of coumarin by liver microsomes from PB-treated gerbils most closely resembled that by human liver microsomes. 7. The gerbil would appear to be a more appropriate animal model than rat for studies to assess the toxicological hazard of coumarin for man.
Fentem
J H
JH
Department of Physiology and Pharmacology, Medical School, Queen's Medical Centre, Nottingham, UK.
Fry
J R
JR
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003374:Coumarins / Q000378:metabolism* / Q000633:toxicity; D005260:Female; D005849:Gerbillinae; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D015262:Xenobiotics / Q000378:metabolism / Q000633:toxicity
D003374:Coumarins; D015262:Xenobiotics; C030123:coumarin