Human and mouse liver coumarin 7-hydroxylases do not metabolize warfarin in vitro.
1. The contribution of human P450 2A6 and mouse P450 2a-5 isoenzymes, both highly active in coumarin 7-hydroxylation, to the metabolism of warfarin was studied in several in vitro systems with human and mouse liver preparations. 2. The reconstituted P450 2a-5 purified from DBA/2 mouse liver did not metabolize warfarin. 3. An anti-P450 2a-5 antibody did not consistently inhibit any of the warfarin biotransformation reactions catalyzed by human or mouse liver microsomes, although coumarin 7-hydroxylation was inhibited by over 90%. 4. In some human microsomal samples, 4- and 8-hydroxylations of warfarin were inhibited to some extent by the anti-P450 2a-5 antibody. 5. Warfarin (less than 1 mM) did not inhibit coumarin 7-hydroxylation by human or mouse liver microsomes in vitro. 6. We conclude that mouse and human coumarin 7-hydroxylases do not oxidise warfarin.
Honkakoski
P
P
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Arvela
P
P
Juvonen
R
R
Lang
M A
MA
Kairaluoma
M
M
Pelkonen
O
O
D000328:Adult; D000368:Aged; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D014859:Warfarin / Q000378:metabolism*
D007527:Isoenzymes; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6