Nakamura Akiko, Nakajima Miki, Yamanaka Hiroyuki, Fujiwara Ryoichi, Yokoi Tsuyoshi
Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Drug Metab Dispos. 2008 Aug;36(8):1461-4. doi: 10.1124/dmd.108.021428. Epub 2008 May 14.
UDP-glucuronosyltransferases (UGTs) are major phase II drug metabolism enzymes that catalyze the glucuronidation of numerous endogenous and exogenous compounds. UGTs are divided into two families, UGT1 and UGT2, based on evolutionary divergence and homology. Nine UGT1A and seven UGT2B functional isoforms have been identified in humans. Glucuronidation occurs mainly in liver but also in various extrahepatic tissues, possibly affecting the pharmacokinetics. In the present study, we comprehensively determined the expression of all functional UGT1A and UGT2B isoforms in normal human tissues including liver, lung, stomach, small intestine, colon, kidney, bladder, adrenal gland, breast, ovary, uterus, and testis by semiquantitative reverse transcription-polymerase chain reaction. In addition, the expressions of these UGTs mRNA in 15 kinds of human tissue-derived cell lines were also analyzed. Many UGT isoforms were abundantly expressed in the liver, gastrointestinal tract, and kidney, supporting previous studies. Interestingly, we found that all UGTs except UGT2B17 were expressed in bladder. In steroid-related tissues, UGTs were expressed in tissue- and isoform-specific manners. Expression profiles in human tissue-derived cell lines were not necessarily consistent with those in corresponding normal tissues. Different expression profiles were observed in distinct cell lines derived from the same organ. The information presented here will be helpful for understanding the glucuronidation in various tissues and for choosing appropriate cell lines for in vitro studies.
UDP-葡萄糖醛酸基转移酶（UGTs）是主要的Ⅱ相药物代谢酶，可催化多种内源性和外源性化合物的葡萄糖醛酸化反应。基于进化差异和同源性，UGTs分为UGT1和UGT2两个家族。在人类中已鉴定出9种UGT1A和7种UGT2B功能异构体。葡萄糖醛酸化反应主要发生在肝脏，但也发生在各种肝外组织中，这可能会影响药物代谢动力学。在本研究中，我们通过半定量逆转录-聚合酶链反应全面测定了正常人体组织（包括肝脏、肺、胃、小肠、结肠、肾脏、膀胱、肾上腺、乳腺、卵巢、子宫和睾丸）中所有功能性UGT1A和UGT2B异构体的表达。此外，还分析了这些UGT mRNA在15种人组织来源细胞系中的表达。许多UGT异构体在肝脏、胃肠道和肾脏中大量表达，这与先前的研究结果一致。有趣的是，我们发现除UGT2B17外，所有UGT均在膀胱中表达。在与类固醇相关的组织中，UGTs以组织和异构体特异性的方式表达。人组织来源细胞系中的表达谱不一定与相应正常组织中的表达谱一致。在源自同一器官的不同细胞系中观察到了不同的表达谱。本文提供的信息将有助于理解各种组织中的葡萄糖醛酸化反应，并有助于选择合适的细胞系进行体外研究。
