Human and mouse liver coumarin 7-hydroxylases do not metabolize warfarin in vitro. |
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Authors: | P Honkakoski P Arvela R Juvonen M A Lang M Kairaluoma and O Pelkonen |
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Institution: | Department of Pharmacology and Toxicology, University of Kuopio, Finland. |
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Abstract: | 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. |
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