The role of the CYP2C9-Leu(359) allelic variant in the tolbutamide polymorphism
The role of the CYP2C9-Leu(359) allelic variant in the tolbutamide polymorphism
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DOI：
10.1097/00008571-199608000-00007
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发表时间：
1996-08-01
期刊：
影响因子：
--
通讯作者：
Goldstein, JA
中科院分区：
文献类型：
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作者：
SullivanKlose, TH;Ghanayem, BI;Goldstein, JA
甲苯磺丁脲在人体内通过细胞色素P450介导的途径发生羟基化，负责这种代谢的主要P450同工酶被认为是CYP 2C 9，群体研究表明存在甲苯磺丁脲的慢代谢者（近似于1/500），提示与2C 9相关的罕见多态性，已经鉴定了2C 9的几种等位基因变体;本研究采用PCR方法扩增了两个慢代谢者CYP 2C 9基因的编码区、内含子-外显子连接区和上游区，并进行了序列测定。其中1例为Leu（359）/Leu（359）纯合子，另1例为Arg（144）/Cys（144）和Ile（359）/Leu（359）杂合子，未检测到2C 9的其他遗传变异。PCR-RFLP分析表明，Arg（144）Tyr（358）Ile（359）Gly（417）是CYP 2C 9的主要等位基因，在高加索裔美国人群体中，较罕见的Leu（359）和Cys（144）等位基因的频率分别为0.06和0.08，在非裔美国人中分别为0.005和0.01。中国台湾人的Leu（359）等位基因频率为0.026，而Cys（144）等位基因在该人群中未检测到。重组酵母表达系统的研究表明，在所有CYP 2C 9等位基因变异体中，Leu（359）变异体对甲苯磺丁脲羟化的Km值最高，Vmac值最低。该等位基因变异体对S-华法林的7-羟基化也具有最高的Km。目前的数据表明，CYP 2C 9的Leu（359）等位基因变异体的发生率可能是甲苯磺丁脲弱代谢型的发生原因。
Tolbutamide undergoes hydroxylation in humans via a cytochrome P450-mediated pathway, The primary P450 isozyme responsible for this metabolism is thought to be CYP2C9, Population studies have indicated the existence of slow metabolizers of tolbutamide (similar to 1 in 500) suggesting a rare polymorphism associated with 2C9, Several allelic variants of 2C9 have been identified; however, the effect of these allelic variations on metabolism in vivo is not established, In the present study, the coding regions, intron-exon junctions, and upstream region of CYP2C9 were amplified by PCR and sequenced in two slow metabolizers. One individual was homozygous for Leu(359)/Leu(359) and the other individual was heterozygous for Arg(144)/Cys(144) and for Ile(359)/Leu(359), No other genetic variations in 2C9 were detected in these individuals, PCR-RFLP tests showed that Arg(144)Tyr(358)Ile(359)Gly(417) is the principle CYP2C9 allele, Frequencies of the rarer Leu(359) and Cys(144) alleles were 0.06 and 0.08, respectively, in a Caucasian-American population and 0.005 and 0.01 respectively in African-Americans. The freqnency of the Leu(359) allele was 0.026 in Chinese-Taiwanese, but the Cys(144) allele was not detected in this population, Studies in a recombinant yeast expression system showed that the Leu(359) variant had the highest K-m and the lowest V-mac for hydroxylation of tolbutamide of all the CYP2C9 allelic variants, This allelic variant also had the highest K-m for the 7-hydroxylation of S-warfarin, The present data suggest that the incidence of the Leu(359) allelic variant of CYP2C9 may account for the occurrence of poor metabolizers of tolbutamide.