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.

Centre of Occupational Diseases National Institute of Public Health Srobárova 48 100 42 Prague 10 Czech Republic

Zobrazit více v PubMed

Chem Biol Interact. 1998 Aug 14;115(1):53-70 PubMed

J Pharmacol Exp Ther. 1994 Mar;268(3):1160-5 PubMed

J Pharmacol Exp Ther. 1995 Nov;275(2):566-75 PubMed

Biochim Biophys Acta. 1994 Apr 13;1205(2):325-35 PubMed

Xenobiotica. 2000 Sep;30(9):857-66 PubMed

Carcinogenesis. 1990 Dec;11(12):2275-9 PubMed

Arch Toxicol. 1993;67(4):237-43 PubMed

Oncogene. 2001 Aug 16;20(36):4995-5004 PubMed

Arch Toxicol. 2000 Oct;74(8):437-46 PubMed

J Biol Chem. 1964 Jul;239:2370-8 PubMed

Xenobiotica. 1995 Jun;25(6):575-84 PubMed

Eur J Cancer. 2000 Aug;36(12):1565-71 PubMed

J Med Chem. 1994 Mar 4;37(5):706-9 PubMed

Cancer Res. 1994 Nov 1;54(21):5543-6 PubMed

Arch Toxicol. 1999 Feb;73(1):33-40 PubMed

Drug Metab Dispos. 1990 Nov-Dec;18(6):895-901 PubMed

Drug Metab Dispos. 1999 Feb;27(2):246-9 PubMed

Nat Biotechnol. 1997 Aug;15(8):784-8 PubMed

Cancer Res. 1981 Jan;41(1):67-72 PubMed

Drug Metab Dispos. 1998 Mar;26(3):229-33 PubMed

Cancer Res. 1994 Jan 15;54(2):386-92 PubMed

Biochem Pharmacol. 1999 Jun 1;57(11):1215-21 PubMed

Drug Metab Dispos. 1998 Oct;26(10):989-92 PubMed

Semin Oncol. 1992 Dec;19(6):646-62 PubMed

Life Sci. 1997;61(2):75-94 PubMed

J Natl Cancer Inst Monogr. 1993;(15):39-46 PubMed

J Biol Chem. 1951 Nov;193(1):265-75 PubMed

Nature. 1979 Feb 22;277(5698):665-7 PubMed

Cancer Res. 1994 Aug 1;54(15):4026-35 PubMed

J Clin Lab Anal. 1997;11(5):287-313 PubMed

Methods Enzymol. 1996;272:145-51 PubMed

Biochem Pharmacol. 1993 Nov 2;46(9):1661-4 PubMed

Drug Metab Dispos. 1995 Nov;23(11):1286-90 PubMed

Xenobiotica. 1998 Feb;28(2):117-26 PubMed

J Am Chem Soc. 1971 May 5;93(9):2325-7 PubMed

Drug Metab Dispos. 2000 Jan;28(1):38-43 PubMed

Curr Med Chem. 2001 Jan;8(1):39-50 PubMed

Anticancer regimens containing third generation taxanes SB-T-121605 and SB-T-121606 are highly effective in resistant ovarian carcinoma model

Transport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cells

Transport and cytotoxicity of paclitaxel, docetaxel, and novel taxanes in human breast cancer cells