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

Abstract

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.

Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity

“…Initial in vitro studies for CYP2C8*3 suggested a lower activity, 31,32 but more recent studies in healthy volunteers have repeatedly demonstrated an increased metabolizing capacity for this allele. [33][34][35][36] In contrast, CYP2C8 haplotype C 35,41 and CYP3A5*3 37 confer a reduced activity.…”

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer

“…The study was initiated based on reports on CYP2C8*3 as having decreased paclitaxel metabolism 20,21 and reports of a functional significance of ABCB1 SNPs with particular interest in C1236T, G2677T/A and C3435T; 22-24 the other candidate SNPs entered the study after it was initiated but the a priori distinction between confirmative and exploratory candidates was kept to meet the issue of multiple testing.…”

Susceptibilidad in vitro de aislamientos colombianos de Plasmodium falciparum a diferentes antipalúdicos

“…Además, la enzima CYP2C8 muestra gran variación entre los individuos en el metabolismo de sustratos (36) y presenta diferentes variantes genéticas (37,38). Todos estos factores pueden ayudar también a explicar la falta de concordancia entre los resultados in vivo e in vitro con la amodiaquina.…”

“…En un estudio de nuestro grupo de 69 pacientes de tres municipios con paludismo de Colombia (Tumaco, Turbo y El Bagre), se encontró la variante CYP2C8*2 en 6% de los pacientes y la mutación R139K de la variante CYP2C8*3 en 3%; dichas variantes aparecieron principalmente en los pacientes en quienes hubo falla terapéutica de la monoterapia con amodiaquina (39); además, se sabe que la presencia de estas mutaciones reduce el metabolismo del paclitaxel (medicamento anticanceroso) y del ácido araquidónico (38).…”