Quantitative Analysis of mRNA and Protein Expression Levels of Aldo-Keto Reductase and Short-Chain Dehydrogenase/Reductase Isoforms in the Human Intestine.

Autor:	Hirosawa K; 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., Fujioka H; 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., Morinaga G; 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., Fukami T; 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., Ishiguro N; 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., Kishimoto W; 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 nmiki@p.kanazawa-u.ac.jp wataru.kishimoto@boehringer-ingelheim.com., Nakase H; 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., Mizuguchi H; 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., Nakajima M; 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 nmiki@p.kanazawa-u.ac.jp wataru.kishimoto@boehringer-ingelheim.com.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2023 Dec; Vol. 51 (12), pp. 1569-1577. Date of Electronic Publication: 2023 Sep 18.
DOI:	10.1124/dmd.123.001402
Abstrakt:	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. (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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