title: Paclitaxel metabolism in rat and human liver microsomes is inhibited by phenolic antioxidants.
abstract: Paclitaxel is an important, recently introduced anti-neoplastic drug. Paclitaxel metabolites are virtually inactive in comparison with the parent drug. The study investigated whether phenolic antioxidants could inhibit metabolic inactivation sufficiently to increase paclitaxel effects. Cytochrome p450 (CYP)-catalysed metabolism of paclitaxel was investigated in rat and human liver microsomes. In rat microsomes, paclitaxel was metabolised mainly to C3'-hydroxypaclitaxel (C3'-OHP), less to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP) and another monohydroxylated paclitaxel. In human liver microsomes, 6alpha-hydroxypaclitaxel (6alpha-OHP), formed by CYP2C8, was the main metabolite, while C3'-OHP, C2-OHP and another product different from di-OHP were minor metabolites, formed by CYP3A4. In individual human livers 6alpha-OHP was formed at 1.8-fold to 13-fold higher rates than C3'-OHP. Kinetic parameters (K(m) and V(max)) of production of various metabolites in rat and human liver microsomes revealed differences between species as well as human individual differences. Nine phenolic antioxidants ((+)-catechin, (-)-epicatechin, fisetin, gallic acid, morin, myricetin, naringenin, quercetin and resveratrol) were tested for inhibition of paclitaxel metabolism. In rat microsomes, resveratrol was more inhibitory than fisetin; the other phenolic antioxidants were without effect. In human microsomes, the inhibiting potency decreased in the order fisetin >quercetin >morin >resveratrol, while the other phenolic antioxidants were not inhibitory; the formation of 6alpha-OHP (CYP2C8) was generally more inhibited than that of C3'-OHP. The inhibition was mostly mixed-type. The results suggest that oral administration of some phenolic substances might increase paclitaxel blood concentrations during chemotherapy.
authors.affiliation: Centre of Occupational Diseases, National Institute of Public Health, Srobárova 48, 100 42, Prague 10, Czech Republic. rvaclavikova@szu.cz
authors.forename: Radka
authors.initials: R
authors.lastname: Václavíková
authors.forename: Stanislav
authors.initials: S
authors.lastname: Horský
authors.forename: Petr
authors.initials: P
authors.lastname: Simek
authors.forename: Ivan
authors.initials: I
authors.lastname: Gut
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D004336:Drug Antagonism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D017239:Paclitaxel / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D010636:Phenols; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D017239:Paclitaxel