人肠道醛酮还原酶和短链脱氢/还原酶同工型的 mRNA 和蛋白表达水平的定量分析。
Quantitative Analysis of mRNA and Protein Expression Levels of Aldo-Keto Reductase and Short-Chain Dehydrogenase/Reductase Isoforms in the Human Intestine.
机构信息
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (K.H., T.F., M.N.) and WPI Nano Life Science Institute (T.F., M.N.), Kanazawa University, Kanazawa, Japan; Department of Pharmacokinetics and Nonclinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (H.F., G.M., N.I., W.K.); Department of Gastroenterology and Hepatology, School of Medicine, Sapporo Medical University, Sapporo, Japan (H.N.); Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (H.M.); Laboratory of Functional Organoid for Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (H.M.); Global Center for Medical Engineering and Informatics (H.M.) and Center for Infectious Disease Education and Research (CiDER) (H.M.), Osaka University, Osaka, Japan.
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (K.H., T.F., M.N.) and WPI Nano Life Science Institute (T.F., M.N.), Kanazawa University, Kanazawa, Japan; Department of Pharmacokinetics and Nonclinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (H.F., G.M., N.I., W.K.); Department of Gastroenterology and Hepatology, School of Medicine, Sapporo Medical University, Sapporo, Japan (H.N.); Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (H.M.); Laboratory of Functional Organoid for Drug Discovery, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (H.M.); Global Center for Medical Engineering and Informatics (H.M.) and Center for Infectious Disease Education and Research (CiDER) (H.M.), Osaka University, Osaka, Japan
出版信息
Drug Metab Dispos. 2023 Dec;51(12):1569-1577. doi: 10.1124/dmd.123.001402. Epub 2023 Sep 18.
Enzymes catalyzing the reduction reaction of xenobiotics are mainly members of the aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase (SDR) superfamilies. The intestine, together with the liver, is responsible for first-pass effects and is an organ that determines the bioavailability of orally administered drugs. In this study, we evaluated the mRNA and protein expression levels of 12 AKR isoforms (AKR1A1, AKR1B1, AKR1B10, AKR1B15, AKR1C1, AKR1C2, AKR1C3, AKR1C4, AKR1D1, AKR1E2, AKR7A2, and AKR7A3) and 7 SDR isoforms (CBR1, CBR3, CBR4, DCXR, DHRS4, HSD11B1, and HSD17B12) in each region of the human intestine using next-generation sequencing and data-independent acquisition proteomics. At both the mRNA and protein levels, most AKR isoforms were highly expressed in the upper regions of the intestine, namely the duodenum and jejunum, and then declined toward the rectum. Among the members in the SDR superfamily, CBR1 and DHRS4 were highly expressed in the upper regions, whereas the expression levels of the other isoforms were almost uniform in all regions. Significant positive correlations between mRNA and protein levels were observed in AKR1A1, AKR1B1, AKR1B10, AKR1C3, AKR7A2, AKR7A3, CBR1, and CBR3. The mRNA level of AKR1B10 was highest, followed by AKR7A3 and CBR1, each accounting for more than 10% of the sum of all AKR and SDR levels in the small intestine. This expression profile in the human intestine was greatly different from that in the human liver, where AKR1C isoforms are predominantly expressed. SIGNIFICANCE STATEMENT: In this study comprehensively determined the mRNA and protein expression profiles of aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase isoforms involved in xenobiotic metabolism in the human intestine and found that most of them are highly expressed in the upper region, where AKR1B10, AKR7A3, and CBR1 are predominantly expressed. Since the intestine is significantly involved in the metabolism of orally administered drugs, the information provided here is valuable for pharmacokinetic studies in drug development.
催化外源物质还原反应的酶主要属于醛酮还原酶（AKR）和短链脱氢酶/还原酶（SDR）超家族。肠道与肝脏一起负责首过效应，是决定口服药物生物利用度的器官。在这项研究中，我们使用下一代测序和非依赖性采集蛋白质组学技术评估了人类肠道各区域中 12 种 AKR 同工型（AKR1A1、AKR1B1、AKR1B10、AKR1B15、AKR1C1、AKR1C2、AKR1C3、AKR1C4、AKR1D1、AKR1E2、AKR7A2 和 AKR7A3）和 7 种 SDR 同工型（CBR1、CBR3、CBR4、DCXR、DHRS4、HSD11B1 和 HSD17B12）的 mRNA 和蛋白表达水平。在 mRNA 和蛋白水平上，大多数 AKR 同工型在上部肠道（十二指肠和空肠）高度表达，然后向直肠方向下降。在 SDR 超家族的成员中，CBR1 和 DHRS4 在上部区域高度表达，而其他同工型的表达水平在所有区域几乎均匀。在 AKR1A1、AKR1B1、AKR1B10、AKR1C3、AKR7A2、AKR7A3、CBR1 和 CBR3 中观察到 mRNA 和蛋白水平之间存在显著的正相关。AKR1B10 的 mRNA 水平最高，其次是 AKR7A3 和 CBR1，分别占小肠中所有 AKR 和 SDR 水平总和的 10%以上。这种在人类肠道中的表达谱与人类肝脏中的表达谱有很大的不同，在人类肝脏中 AKR1C 同工型主要表达。
意义陈述：在这项研究中，我们全面确定了人类肠道中外源物质代谢中涉及的醛酮还原酶（AKR）和短链脱氢酶/还原酶同工型的 mRNA 和蛋白表达谱，发现它们大多数在上部区域高度表达，其中 AKR1B10、AKR7A3 和 CBR1 是主要表达的。由于肠道在口服药物的代谢中具有重要作用，因此这里提供的信息对于药物开发中的药代动力学研究具有重要价值。
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