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首页> 外文期刊>Pharmacogenetics >Tissue distribution and interindividual variation in human UDP-glucuronosyltransferase activity: relationship between UGT1A1 promoter genotype and variability in a liver bank.
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Tissue distribution and interindividual variation in human UDP-glucuronosyltransferase activity: relationship between UGT1A1 promoter genotype and variability in a liver bank.

机译：人UDP-葡萄糖醛酸转移酶活性的组织分布和个体间差异：UGT1A1启动子基因型与肝库变异性之间的关系。

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摘要

The variability in a liver bank and tissue distribution of three probe UDP-glucuronosyltransferase (UGT) activities were determined as a means to predict interindividual differences in expression and the contribution of extrahepatic metabolism to presystemic and systemic clearance. Formation rates of acetaminophen-O-glucuronide (APAPG), morphine-3-glucuronide (M3G), and oestradiol-3-glucuronide (E3G) as probes for UGT1A6, 2B7, and 1A1, respectively, were determined in human kidney, liver, and lung microsomes, and in microsomes from intestinal mucosa corresponding to duodenum, jejunum and ileum. While formation of E3G and APAPG were detectable in human kidney microsomes, M3G formation rates from kidney microsomes approached the levels seen in liver, indicating significant expression of UGT2B7. Interestingly, rates of E3G formation in human intestine exceeded the hepatic rates by several fold, while APAPG and M3G formation rates were low. The intestinal apparent Km value for E3G formation was essentially identical to that seen in liver, consistent with intestinal UGT1A1 expression. No UGT activities were observed in lung. Variability in APAPG and M3G activity across a bank of 20 human livers was modest (< or = 7-fold), compared to E3G formation, which varied approximately 30-fold. The E3G formation rates were found to segregate by UGT1A1 promoter genotype, with wild-type (TA)6 rates significantly greater than homozygous mutant (TA)7 individuals. Kinetic analyses were performed to demonstrate that the promoter mutation altered apparent Vmax without significantly affecting apparent Km. These results suggest that glucuronidation, and specifically UGT1A1 activity, can profoundly contribute to intestinal first pass metabolism and interindividual variability due to the expression of common allelic variants.
机译：确定了三种探针UDP-葡萄糖醛酸转移酶（UGT）活性在肝库中的变异性和组织分布，作为预测个体间表达差异和肝外代谢对系统前和系统清除的贡献的手段。确定了在人肾，肝，肾，肝，肾，肾，肝，肾等和肺微粒体，以及来自肠粘膜的微粒体，对应于十二指肠，空肠和回肠。虽然在人肾微粒体中可检测到E3G和APAPG的形成，但来自肾微粒体的M3G形成速率接近肝脏中观察到的水平，表明UGT2B7的表达显着。有趣的是，人肠中E3G的形成速率超过肝脏的几倍，而APAPG和M3G的形成率却很低。 E3G形成的肠表观Km值与肝脏中观察到的Km值基本相同，与肠UGT1A1表达一致。在肺中未观察到UGT活性。与E3G的形成相差约30倍，横跨20个人肝的APAPG和M3G活性的差异较小（<或= 7倍）。发现E3G形成速率是通过UGT1A1启动子基因型分离的，其中野生型（TA）6的速率显着高于纯合突变体（TA）7的个体。进行动力学分析以证明启动子突变改变了表观Vmax，而没有明显影响表观Km。这些结果表明，由于常见的等位基因变体的表达，葡萄糖醛酸化，特别是UGT1A1的活性，可以对肠道首过代谢和个体间差异产生深远的影响。

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