In vivo evaluation of coumarin and nicotine as probe drugs to predict the metabolic capacity of CYP2A6 due to genetic polymorphism in Thais.
In vivo evaluation of coumarin and nicotine as probe drugs to predict the metabolic capacity of CYP2A6 due to genetic polymorphism in Thais.
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DOI：
10.2133/dmpk.21.475
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发表时间：
2006
影响因子：
2.1
通讯作者：
S. Peamkrasatam;K. Sriwatanakul;K. Kiyotani;M. Fujieda;H. Yamazaki;T. Kamataki;K. Yoovathaworn
中科院分区：
文献类型：
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作者：
S. Peamkrasatam;K. Sriwatanakul;K. Kiyotani;M. Fujieda;H. Yamazaki;T. Kamataki;K. Yoovathaworn
在 120 名健康泰国人中估计了 CYP2A6 对尼古丁和香豆素催化活性的分布特征与报告的 CYP2A6 变异等位基因的频率分布之间的关联。根据尿液中排泄的 7-羟基香豆素 (7-OHC) 量和血浆中可替宁/尼古丁比率分类的受试者分布明显是双峰的。然而，香豆素和尼古丁明显代谢不良的人数不同。香豆素和尼古丁体内分布的个体差异与CYP2A6基因多态性密切相关。受试者尿液中 7-OHC 排泄率与血浆中可替宁/尼古丁比值之间存在密切相关性（R=0.92，p<0.001）。本研究中发现的CYP2A6等位基因频率为：CYP2A6*1A=32%（95% CI, 22.1-39.4%）、CYP2A6*1B=27%（95% CI, 19.4-33.5%）、CYP2A6*9=20%（95% CI, 17.6-23.3%）、 CYP2A6*4=14%（95% CI，9.6-17.8%），CYP2A6*7=5%（95% CI，3.7-9.4%），CYP2A6*10=2%（95% CI，0.8-5.1%）。与其他基因型相比，携带 CYP2A6*1A/*1B 的受试者被发现具有更高的 7-OHC 排泄率，以及血浆中更高的可替宁/尼古丁比率。相比之下，携带 CYP2A6*4/*7 和 CYP2A6*7/*7 的受试者几乎没有任何可替宁形成，而尿液中 7-OHC 仍然可检测到。 CYP2A6*9 等位基因明显导致酶活性降低。尽管不存在 CYP2A6*10 等位基因的纯合子，但 CYP2A6*10 等位基因的存在显着降低了酶活性。本研究的结果表明，使用尼古丁和香豆素对 CYP2A6 进行体内表型分析在代谢上并不等效。根据其特异性，尼古丁是一种更好的探针，而香豆素对于常规 CYP2A6 表型分析仍然有价值，因为该测试采用非侵入性方法。
The association between the distribution characteristics of CYP2A6 catalytic activities toward nicotine and coumarin, and the frequency distribution of CYP2A6 variant alleles reported was estimated in 120 healthy Thais. The distributions of the subjects as classified by the amounts of 7-hydroxycoumarin (7-OHC) excreted in the urine and by cotinine/nicotine ratio in the plasma were clearly bimodal. However, the numbers of apparently poor metabolizers for coumarin and nicotine were different. The inter-individual variability in the in vivo dispositions of coumarin and nicotine closely related to the CYP2A6 genetic polymorphism. There was a close correlation between the rate of 7-OHC excretion in the urine and cotinine/nicotine ratio in the plasma among subjects (R=0.92, p<0.001). The frequency of CYP2A6 allele found in the present study was: CYP2A6*1A=32% (95% CI, 22.1-39.4%), CYP2A6*1B=27% (95% CI, 19.4-33.5%), CYP2A6*9=20% (95% CI, 17.6-23.3%), CYP2A6*4=14% (95% CI, 9.6-17.8%), CYP2A6*7=5% (95% CI, 3.7-9.4%), CYP2A6*10=2% (95% CI, 0.8-5.1%). Subjects having CYP2A6*1A/*1B were found to have a higher rate of 7-OHC excretion, as well as a higher cotinine/nicotine ratio in the plasma compared with those of the other genotypes. In contrast, subjects with CYP2A6*4/*7 and CYP2A6*7/*7 almost lacked any cotinine formation, whereas urinary 7-OHC was still detectable. CYP2A6*9 allele clearly resulted in reduced enzyme activities. Despite the absence of the homozygote for CYP2A6*10 allele, the presence of CYP2A6*10 allele significantly decreased the enzyme activities. The results of the present study demonstrate that in vivo phenotyping of CYP2A6 using nicotine and coumarin are not metabolically equivalent. Nicotine is a better probe according to its specificity, while coumarin is still valuable to be used for a routine CYP2A6 phenotyping since the test employs a non-invasive method.