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Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid

Dai, Ding; Zeldin, Darryl C.; Blaisdell, Joyce A.; Chanas, Brian; Coulter, Sherry J.; Ghanayem, Burhan I.; Goldstein, Joyce A.

Original Article

Cytochrome P450 (CYP) 2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (Taxol). It is also the predominant P450 responsible for the metabolism of arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs) in human liver and kidney. In this study, we describe two new CYP2C8 alleles containing coding changes:CYP2C8*2 has an Ile269Phe substitution in exon 5 and CYP2C8*3 includes both Arg139Lys and Lys399Arg amino acid substitutions in exons 3 and 8. CYP2C8*2 was found only in African-Americans, while CYP2C8*3 occurred primarily in Caucasians. Neither occurred in Asians. The frequency of the CYP2C8*2 allele was 0.18 in African-Americans, and that of CYP2C8*3 was 0.13 in Caucasians. CYP2C8*1 (wild-type), CYP2C8*2 and CYP2C8*3 cDNAs were expressed in Escherichia coli, and the ability of these enzymes to metabolize both paclitaxel and arachidonic acid was assessed. Recombinant CYP2C8*3 was defective in the metabolism of both substrates. The turnover number of CYP2C8*3 for paclitaxel was 15% of CYP2C8*1. CYP2C8*2 had a two-fold higher Km and two-fold lower intrinsic clearance for paclitaxel than CYP2C8*1. CYP2C8*3 was also markedly defective in the metabolism of arachidonic acid to 11,12- and 14,15-EET (turnover numbers 35–40% that of CYP2C8*1). Thus, CYP2C8*3 is defective in the metabolism of two important CYP2C8 substrates: the anticancer drug paclitaxel and the physiologically important compound arachidonic acid. This polymorphism has important clinical and physiological implications in individuals homozygous for this allele.

Laboratories of Pharmacology and Chemistry and Pulmonary and Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

Received 6 November 2000; accepted 12 February 2001

Correspondence to Dr Joyce A. Goldstein, MD A303, PO Box 12233, NIEHS, RTP, NC 27709, USA Tel: +1 919 541 4495; fax: +1 919 541 3647; e-mail: goldste1@niehs. nih.gov

1CYP2C8*1 represents the first wild-type CYP2C8 gene sequence reported (Klose, 1999). CYP2C8*2 differs from CYP2C8*1 by a C to T in IVS1-37, a G to A in IVS2-36, the insertion of a T in IVS2-13, an A to T at bp 805 in exon 5 coding for Ile269Phe, a T to A at IVS7+49, an A to G at IVS8-92, and a C to T in IVS9+24. CYP2C8*3 differs from CYP2C8*1 by a C to T at IVS1-37, a G to A at IVS2-36, a G to A at bp 416 in exon 3 coding for Arg139Lys, a T to A at IVS7+49, an A to G at bp 1996 in exon 8 coding for Lys399Arg, and a C to T at IVS9+24. The linkages were obtained from individuals homozygous for the Ile269Phe change (CYP2C8*2) and the Arg139Lys, Lys399Arg (CYP2C8*3) mutations.

© 2001 Lippincott Williams & Wilkins, Inc.