Glucuronidation of SN-38 serves as an important metabolic pathway in determining the toxic effects of irinotecan. The role of UDP-glucuronosyltransferases (UGT) 1A9 in SN-38 glucuronidation pathway is very confusing. This study re-investigates the pathway through testing effects of bovine serum albumin (BSA) and the selective inhibitor on SN-38 glucuronidation in pooled human liver microsomes (HLM) and recombinant UGT1A1/UGT1A9. For UGT1A1, SN-38 glucuronidation was little affected by BSA. Whether in the presence of BSA or not, the reactions both obey Michaelis-Menten kinetics with closed Vmax/Km values. For UGT1A9 and HLM, BSA can significantly accelerate SN-38 glucuronidation activities and similar effects are further observed on kinetic patterns. In the absence of BSA, reactions by HLM and UGT1A9 both display substrate inhibition kinetics. When BSA is included in the incubations, the reactions exhibit Michaelis-Menten kinetics. To get the true contribution of UGT1A9 in SN-38 glucuronidation, a relative activity factor (RAF) approach was additionally used. It is suggested that UGT1A9 and 1A1 contribute equally to SN-38 glucuronidation in HLM. Furthermore, in the presence of BSA, magnolol, a selective UGT1A9 inhibitor, displays moderate inhibition against HLM. Results together conclude that UGT1A9 serves as an additional important contributor to hepatic SN-38 glucuronidation.

中文翻译：

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SN-38葡萄糖醛酸化的新见解：UDP葡萄糖醛酸糖基转移酶1A9的重要作用的证据。

SN-38的葡萄糖醛酸化作用是确定伊立替康毒性作用的重要代谢途径。UDP-葡糖醛酸糖基转移酶（UGT）1A9在SN-38葡糖醛酸化途径中的作用非常令人困惑。这项研究通过测试牛血清白蛋白（BSA）和选择性抑制剂对合并人肝微粒体（HLM）和重组UGT1A1 / UGT1A9中SN-38糖醛酸糖苷化的作用，重新研究了该途径。对于UGT1A1，SN-38葡萄糖醛酸苷化几乎不受BSA影响。无论是否存在BSA，反应均服从具有封闭的Vmax / Km值的Michaelis-Menten动力学。对于UGT1A9和HLM，BSA可以显着加速SN-38葡萄糖醛酸化活性，并且在动力学模式上进一步观察到类似的作用。在没有BSA的情况下，HLM和UGT1A9的反应均显示底物抑制动力学。当孵育中包含BSA时，反应显示出Michaelis-Menten动力学。为了获得UGT1A9在SN-38葡萄糖醛酸糖化中的真正贡献，还使用了相对活性因子（RAF）方法。建议UGT1A9和1A1对HLM中的SN-38葡糖醛酸糖化具有同等作用。此外，在BSA的存在下，厚朴酚（一种选择性的UGT1A9抑制剂）表现出对HLM的中等抑制作用。结果共同得出结论，UGT1A9是肝SN-38葡萄糖醛酸糖化的另一个重要贡献者。在BSA存在下，厚朴酚（一种选择性的UGT1A9抑制剂）表现出对HLM的中等抑制作用。结果共同得出结论，UGT1A9是肝SN-38葡萄糖醛酸糖化的另一个重要贡献者。在BSA存在下，厚朴酚（一种选择性的UGT1A9抑制剂）表现出对HLM的中等抑制作用。结果一起得出结论，UGT1A9是肝SN-38葡萄糖醛酸糖化的另一个重要贡献者。