肝脏微粒体和表达的 UGT 酶对雌二醇葡萄糖醛酸化作用的动力学特征:有机溶剂的影响

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Caimei Wu, Meixue Luo, Dihao Xie, Simin Zhong, Jiahao Xu, Danyi Lu
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引用次数: 0

摘要

背景和目的:为了评估尿苷-5'-二磷酸-葡萄糖醛酸基转移酶 1A1(UGT1A1)在异生物/药物代谢中的作用,通常会对 17β-雌二醇(雌二醇)进行体外葡萄糖醛酸化。本研究的目的是确定四种常用有机溶剂[即二甲基亚砜(DMSO)、甲醇、乙醇和乙腈]对雌二醇葡萄糖醛酸化动力学的影响:方法:利用表达的 UGT 酶和人与动物的肝微粒体测定有机溶剂对雌二醇葡萄糖醛酸化的影响:结果:在人类肝脏微粒体(HLM)中,甲醇、乙醇和乙腈显著改变了雌二醇葡萄糖醛酸化动力学,其Vmax值和CLmax值分别增加了2.6倍和2.8倍。据推断,HLM 中雌二醇葡萄糖醛酸化作用的改变是由于 UGT1A1 和 UGT2B7 的代谢活性增强所致,它们在两个葡萄糖醛酸化位置的活性不同。有机溶剂对雌二醇葡萄糖醛酸化的影响具有葡萄糖醛酸化位置特异性、同工酶特异性和溶剂特异性。此外,乙醇和乙腈都更倾向于改变雌二醇在动物肝脏微粒体中的葡萄糖醛酸化活性:结论:甲醇、乙醇和乙腈等有机溶剂在调节雌二醇的葡萄糖醛酸化过程中表现出巨大的潜力。二甲基亚砜是最合适的溶剂,因为它对雌二醇葡萄糖醛酸化作用的影响最小。研究人员在评估新化学实体的代谢时应谨慎选择适当的溶剂,以获得准确的结果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Kinetic Characterization of Estradiol Glucuronidation by Liver Microsomes and Expressed UGT Enzymes: The Effects of Organic Solvents.

Kinetic Characterization of Estradiol Glucuronidation by Liver Microsomes and Expressed UGT Enzymes: The Effects of Organic Solvents.

Background and objective: In vitro glucuronidation of 17β-estradiol (estradiol) is often performed to assess the role of uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) in xenobiotic/drug metabolism. The objective of this study was to determine the effects of four commonly used organic solvents [i.e., dimethyl sulfoxide (DMSO), methanol, ethanol, and acetonitrile] on the glucuronidation kinetics of estradiol, which can be glucuronidated at C3 and C17 positions.

Methods: The impacts of organic solvents on estradiol glucuronidation were determined by using expressed UGT enzymes and liver microsomes from both human and animals.

Results: In human liver microsomes (HLM), methanol, ethanol, and acetonitrile significantly altered estradiol glucuronidation kinetics with increased Vmax (up to 2.6-fold) and CLmax (up to 2.8-fold) values. Altered estradiol glucuronidation in HLM was deduced to be attributed to the enhanced metabolic activities of UGT1A1 and UGT2B7, whose activities differ at the two glucuronidation positions. The effects of organic solvents on estradiol glucuronidation were glucuronidation position-, isozyme-, and solvent-specific. Furthermore, both ethanol and acetonitrile have a greater tendency to modify the glucuronidation activity of estradiol in animal liver microsomes.

Conclusion: Organic solvents such as methanol, ethanol, and acetonitrile showed great potential in adjusting the glucuronidation of estradiol. DMSO is the most suitable solvent due to its minimal influence on estradiol glucuronidation. Researchers should be cautious in selecting appropriate solvents to get accurate results when assessing the metabolism of a new chemical entity.

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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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