RT Journal Article
SR Electronic
T1 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
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2022-001037
DO 10.1124/dmd.122.001037
A1 Hiroyuki Ichida
A1 Tatsuki Fukami
A1 Keito Amai
A1 Kohei Suzuki
A1 Kenji Mishiro
A1 Shiori Takano
A1 Wataru Obuchi
A1 Zhengyu Zhang
A1 Akiko Watanabe
A1 Masataka Nakano
A1 Kengo Watanabe
A1 Miki Nakajima
YR 2022
UL http://dmd.aspetjournals.org/content/early/2022/10/30/dmd.122.001037.abstract
AB 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.