Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates.
Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates.
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DOI：
10.1097/00008571-200108000-00003
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发表时间：
2001-08
期刊：
影响因子：
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通讯作者：
Yamini Ramamoorthy;R. Tyndale;E. Sellers
中科院分区：
文献类型：
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作者：
Yamini Ramamoorthy;R. Tyndale;E. Sellers
CYP2D6参与了几类药物的代谢，包括三环类抗抑郁药、选择性5-羟色胺再摄取抑制剂和各种苯丙胺。CYP2D6*10是一种等位基因变异，产生一种带有Pro34Ser和Ser486Thr氨基酸替换的酶。大约75%的亚洲人拥有*10等位基因。我们试图在使用各种底物和抑制剂的杆状病毒表达系统中进一步研究CYP2D6.10的体外催化特性，并与野生型CYP2D6.1进行比较。右美沙芬(DEX)、对甲氧基苯丙胺、1-甲基-4-苯基-1，2，3，6-四氢吡啶和(+/-)3，4-亚甲基二氧基甲基苯丙胺(MDMA)的内禀清除度(Vmax/Km)分别为50、34、22和123。CYP2D6底物阿米替林和(+)和(-)甲基苯丙胺(MAMP)都是对羟基和N-脱甲基(NDM)。对羟基化的本征清除量*1/*10分别为42、30和67，NDM分别为60、120和157，说明了MAMP的化学途径和对映体选择性。很明显，(+)和(-)MAMP、NDM和MDMA去甲基化在CYP2D6.10中差异最显著。以地塞米松为底物，KI(*10)/KI(*1)的比值为：布地平(1.3)、司马汀(1.6)、去甲异喹(8.1)、氟西汀(16)、去氟西汀(30)、帕罗西汀(14)、MDMA(21)和MMDA-2(7.1)。综上所述，这些数据表明，与CYP2D6*1/*1个体相比，预计CYP2D6*10/*10个体可能需要不同的药物剂量；并且显示出对毒性、相互作用风险的改变的敏感性，就苯丙胺而言，药物依赖性和毒性。
CYP2D6 is involved in the metabolism of several classes of drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors and various amphetamines. CYP2D6*10 is an allelic variant, producing an enzyme with Pro34Ser and Ser486Thr amino acid substitutions. Approximately 75% of Asians possess the *10 allele. We sought to further characterize CYP2D6.10 catalytically in vitro in a baculovirus expression system using various substrates and inhibitors, in comparison to CYP2D6.1 (wild-type). Using dextromethorphan (DEX), P-methoxyamphetamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and (+/-)3,4-methylenedioxymethamphetamine (MDMA), the ratios of intrinsic clearance (Vmax/Km) of *1 to *10 were 50, 34, 22 and 123, respectively. The CYP2D6 substrates amitriptyline, and (+) and (-) methamphetamine (MAMP) are both p-hydroxylated and N-demethylated (NDM). The intrinsic clearance *1/*10 ratios were 42, 30 and 67 for the p-hydroxylation; and 60, 120 and 157 for the NDM, respectively, illustrating chemical pathway and enantiomeric selectivity for MAMP. It was apparent that (+) and (-) MAMP NDM and MDMA demethylenation were most significantly different in CYP2D6.10. Using DEX as the substrate, the ratios of Ki(*10)/Ki(*1) for inhibitors were: budipine (1.3), sparteine (1.6), debrisoquine (8.1), fluoxetine (16), norfluoxetine (30), paroxetine (14), MDMA (21) and MMDA-2 (7.1), indicating that CYP2D6.10 shows drug-specific altered susceptibility to inhibition. Taken together, these data suggest that CYP2D6*10/*10 individuals may be expected to require different drug doses; and show altered susceptibility to toxicity, interaction risk and, in the case of the amphetamines, drug dependence and toxicity compared to CYP2D6*1/*1 individuals.