Roles of human liver cytochrome P450 3A4 and 1A2 enzymes in the oxidation of myristicin.
The aim of this work was to identify the form(s) of human liver cytochrome P450 (CYP) involved in the hepatic transformation of myristicin to its major metabolite, 5-allyl-1-methoxy-2,3-dihydroxybenzene. When microsomes prepared from different human liver samples were compared, the activity of 5-allyl-1-methoxy-2,3-dihydroxybenzene formation was well correlated (r(2)=0.87) with nifedipine oxidation (a marker of CYP3A4). With a microsomal sample having high CYP3A4 activity, microsomal oxidation of myristicin to the major metabolite (5-allyl-1-methoxy-2,3-dihydroxybenzene) was markedly inhibited by gestodene and ketoconazole, selective inhibitors of CYP3A enzymes, but not by any of several other P450 inhibitors. Antibodies raised against CYPs 3A4 and 1A2 could also inhibit the oxidation of myristicin, but antibodies recognizing other CYPs had no effect. The oxidation of myristicin to 5-allyl-1-methoxy-2,3-dihydroxybenzene was catalyzed by purified bacterial recombinant CYPs 3A4 and 1A2. These results provide evidence that CYP3A4 (and possibly other CYP3A enzymes) and CYP1A2 play roles in the formation of the major metabolite, 5-allyl-1-methoxy-2,3-dihydroxybenzene.
Yun
Chul-Ho
CH
Department of Genetic Engineering, Pai-Chai University, 439-6 Doma-dong, Seo-ku, Taejon 302-735, South Korea. chyun@mail.pcu.ac.kr
Lee
Hye Suk
HS
Lee
Hee-Yong
HY
Yim
Sung-Kun
SK
Kim
Keon-Hee
KH
Kim
Eunhee
E
Yea
Sung-Su
SS
Guengerich
F Peter
FP
D000475:Alkenes / Q000378:metabolism; D000081248:Allylbenzene Derivatives; D019138:Antibodies, Blocking / Q000494:pharmacology; D001554:Benzene / Q000378:metabolism; D001555:Benzene Derivatives; D001593:Benzyl Compounds; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004148:Dioxolanes / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009652:Norpregnenes / Q000494:pharmacology; D010084:Oxidation-Reduction; D011748:Pyrogallol / Q000031:analogs & derivatives
C471354:5-allyl-1-methoxy-2,3-dihydroxybenzene; D000475:Alkenes; D000081248:Allylbenzene Derivatives; D019138:Antibodies, Blocking; D001555:Benzene Derivatives; D001593:Benzyl Compounds; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004148:Dioxolanes; D004791:Enzyme Inhibitors; D009652:Norpregnenes; D011748:Pyrogallol; C005246:myristicin; C033273:Gestodene; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D001554:Benzene; D007654:Ketoconazole