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

Humans Aldo-Keto Reductases / genetics RNA, Messenger / genetics Short Chain Dehydrogenase-Reductases Aldehyde Reductase / genetics Protein Isoforms / genetics Oxidoreductases / genetics Intestines

Journal

Drug metabolism and disposition: the biological fate of chemicals
ISSN: 1521-009X
Titre abrégé: Drug Metab Dispos
Pays: United States
ID NLM: 9421550

Informations de publication

Date de publication:
Dec 2023
Historique:
received: 30 05 2023
accepted: 13 09 2023
medline: 16 11 2023
pubmed: 19 9 2023
entrez: 18 9 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1124/dmd.123.001402 PMID: 37722844
pubmed: 37722844
pii: dmd.123.001402
doi: 10.1124/dmd.123.001402
doi:

Substances chimiques

Aldo-Keto Reductases EC 1.1.1.-
RNA, Messenger 0
Short Chain Dehydrogenase-Reductases EC 1.1.1.-
Aldehyde Reductase EC 1.1.1.21
Protein Isoforms 0
Oxidoreductases EC 1.-
AKR1B1 protein, human EC 1.1.1.21

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1569-1577

Informations de copyright

Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.

Auteurs

Keiya 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.

Hijiri 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.

Gaku 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.

Tatsuki 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.

Naoki 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.

Wataru 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.

Hiroshi 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.

Hiroyuki 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.
ORCID: 0000-0003-0594-8178

Miki 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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Quantitative Analysis of mRNA and Protein...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Alcohol oxidoreductases › NAD (+) and NADP (+) dependent Alcohol oxidoreductases › Aldo-keto reductases › Quantitative Analysis of mRNA and Protein...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN messager › Quantitative Analysis of mRNA and Protein...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Alcohol oxidoreductases › NAD (+) and NADP (+) dependent Alcohol oxidoreductases › Short chain dehydrogenase-reductases › Quantitative Analysis of mRNA and Protein...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Alcohol oxidoreductases › NAD (+) and NADP (+) dependent Alcohol oxidoreductases › Aldo-keto reductases › Aldose reductase › Quantitative Analysis of mRNA and Protein...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Isoformes de protéines › Quantitative Analysis of mRNA and Protein...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Oxidoreductases › Quantitative Analysis of mRNA and Protein...
questionsmedicales.fr › Système digestif › Tube digestif › Intestins › Quantitative Analysis of mRNA and Protein...