Quantitative Evaluation of the Contribution of Each Aldo-Keto Reductase and Short-Chain Dehydrogenase/Reductase Isoform to Reduction Reactions of Compounds Containing a Ketone Group in the Human Liver.

Autor:	Ichida H; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (H.I., T.F., K.A., K.S., S.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Ma.N., Mi.N.), and Institute for Frontier Science Initiative (K.M.), Kanazawa University, Kanazawa, Japan; and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan (W.O., Z.Z., A.W., K.W.)., Fukami T; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (H.I., T.F., K.A., K.S., S.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Ma.N., Mi.N.), and Institute for Frontier Science Initiative (K.M.), Kanazawa University, Kanazawa, Japan; and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan (W.O., Z.Z., A.W., K.W.) tatsuki@p.kanazawa-u.ac.jp., Amai K; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (H.I., T.F., K.A., K.S., S.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Ma.N., Mi.N.), and Institute for Frontier Science Initiative (K.M.), Kanazawa University, Kanazawa, Japan; and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan (W.O., Z.Z., A.W., K.W.)., Suzuki K; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (H.I., T.F., K.A., K.S., S.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Ma.N., Mi.N.), and Institute for Frontier Science Initiative (K.M.), Kanazawa University, Kanazawa, Japan; and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan (W.O., Z.Z., A.W., K.W.)., Mishiro K; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (H.I., T.F., K.A., K.S., S.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Ma.N., Mi.N.), and Institute for Frontier Science Initiative (K.M.), Kanazawa University, Kanazawa, Japan; and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan (W.O., Z.Z., A.W., K.W.)., Takano S; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (H.I., T.F., K.A., K.S., S.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Ma.N., Mi.N.), and Institute for Frontier Science Initiative (K.M.), Kanazawa University, Kanazawa, Japan; and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan (W.O., Z.Z., A.W., K.W.)., Obuchi W; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (H.I., T.F., K.A., K.S., S.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Ma.N., Mi.N.), and Institute for Frontier Science Initiative (K.M.), Kanazawa University, Kanazawa, Japan; and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan (W.O., Z.Z., A.W., K.W.)., Zhang Z; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (H.I., T.F., K.A., K.S., S.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Ma.N., Mi.N.), and Institute for Frontier Science Initiative (K.M.), Kanazawa University, Kanazawa, Japan; and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan (W.O., Z.Z., A.W., K.W.)., Watanabe A; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (H.I., T.F., K.A., K.S., S.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Ma.N., Mi.N.), and Institute for Frontier Science Initiative (K.M.), Kanazawa University, Kanazawa, Japan; and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan (W.O., Z.Z., A.W., K.W.)., Nakano M; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (H.I., T.F., K.A., K.S., S.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Ma.N., Mi.N.), and Institute for Frontier Science Initiative (K.M.), Kanazawa University, Kanazawa, Japan; and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan (W.O., Z.Z., A.W., K.W.)., Watanabe K; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (H.I., T.F., K.A., K.S., S.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Ma.N., Mi.N.), and Institute for Frontier Science Initiative (K.M.), Kanazawa University, Kanazawa, Japan; and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan (W.O., Z.Z., A.W., K.W.)., Nakajima M; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (H.I., T.F., K.A., K.S., S.T., Ma.N., Mi.N.), WPI Nano Life Science Institute (WPI-NanoLSI) (T.F., Ma.N., Mi.N.), and Institute for Frontier Science Initiative (K.M.), Kanazawa University, Kanazawa, Japan; and Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan (W.O., Z.Z., A.W., K.W.).
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2023 Jan; Vol. 51 (1), pp. 17-28. Date of Electronic Publication: 2022 Oct 30.
DOI:	10.1124/dmd.122.001037
Abstrakt:	Enzymes of the aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase superfamilies are involved in the reduction of compounds containing a ketone group. In most cases, multiple isoforms appear to be involved in the reduction of a compound, and the enzyme(s) that are responsible for the reaction in the human liver have not been elucidated. The purpose of this study was to quantitatively evaluate the contribution of each isoform to reduction reactions in the human liver. Recombinant cytosolic isoforms were constructed, i.e., AKR1C1, AKR1C2, AKR1C3, AKR1C4, and carbonyl reductase 1 (CBR1), and a microsomal isoform, 11 β -hydroxysteroid dehydrogenase type 1 (HSD11B1), and their contributions to the reduction of 10 compounds were examined by extrapolating the relative expression of each reductase protein in human liver preparations to recombinant systems quantified by liquid chromatography-mass spectrometry. The reductase activities for acetohexamide, doxorubicin, haloperidol, loxoprofen, naloxone, oxcarbazepine, and pentoxifylline were predominantly catalyzed by cytosolic isoforms, and the sum of the contributions of individual cytosolic reductases was almost 100%. Interestingly, AKR1C3 showed the highest contribution to acetohexamide and loxoprofen reduction, although previous studies have revealed that CBR1 mainly metabolizes them. The reductase activities of bupropion, ketoprofen, and tolperisone were catalyzed by microsomal isoform(s), and the contributions of HSD11B1 were calculated to be 41%, 32%, and 104%, respectively. To our knowledge, this is the first study to quantitatively evaluate the contribution of each reductase to the reduction of drugs in the human liver. SIGNIFICANCE STATEMENT: To our knowledge, this is the first study to determine the contribution of aldo-keto reductase (AKR)-1C1, AKR1C2, AKR1C3, AKR1C4, carbonyl reductase 1, and 11 β -hydroxysteroid dehydrogenase type 1 to drug reductions in the human liver by utilizing the relative expression factor approach. This study found that AKR1C3 contributes to the reduction of compounds at higher-than-expected rates. (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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