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.