@article {IchidaDMD-AR-2022-001037, author = {Hiroyuki Ichida and Tatsuki Fukami and Keito Amai and Kohei Suzuki and Kenji Mishiro and Shiori Takano and Wataru Obuchi and Zhengyu Zhang and Akiko Watanabe and Masataka Nakano and Kengo Watanabe and Miki Nakajima}, title = {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}, elocation-id = {DMD-AR-2022-001037}, year = {2022}, doi = {10.1124/dmd.122.001037}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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, 11β-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 (MS)/MS. 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 AKR1C1, AKR1C2, AKR1C3, AKR1C4, CBR1, and HSD11B1 to drug reductions in the human liver by utilizing the REF approach. We found that AKR1C3 contributes to the reduction of compounds at higher than expected rates.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2022/10/30/dmd.122.001037}, eprint = {https://dmd.aspetjournals.org/content/early/2022/10/30/dmd.122.001037.full.pdf}, journal = {Drug Metabolism and Disposition} }