文章基本信息

标题：Non-synonymous Single Nucleotide Alterations Found in the CYP2C8 Gene Result in Reduced in Vitro Paclitaxel Metabolism
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作者：Akiko SOYAMA ; Yoshiro SAITO ; Nobumitsu HANIOKA 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2001
卷号：24
期号：12
页码：1427-1430
DOI：10.1248/bpb.24.1427
出版社：The Pharmaceutical Society of Japan
摘要：By sequencing genomic DNA from 73 established cell lines derived from Japanese individuals, we detected 9 single nucleotide polymorphisms (SNPs) in the CYP2C8 gene. Of them, 3 exonic SNPs resulted in amino acid alterations (g416a, R139K; a1196g, K399R; c1210g, P404A). The first two alterations were detected concurrently in one cell line and thought to be the same as CYP2C8^*3. To examine the effects of these amino acid alterations on CYP2C8 function, wild-type and four types of variant CYP2C8 cDNA constructs (R139K, K399R, R139K/K399R and P404A) were transfected into Hep G2 cells and their paclitaxel 6α-hydroxylase activities were determined in vitro. K_m values were not significantly different from that of the wild-type in any of the variants studied. The variant R139K/K399R showed reduced values for V_max and clearance (V_max/K_m) similar to those of its single variant, R139K. The variant P404A also showed a significantly lowered clearance due to reduced level of protein expression. These results suggest that not only the double variant (R139K/K399R, CYP2C8^*3) but also our novel variant P404A in the CYP2C8 gene are less efficient in paclitaxel metabolism.
关键词：CYP2C8;polymorphism;paclitaxel;metabolism