Identification of HSD17B12 as an enzyme catalyzing drug reduction reactions through investigation of nabumetone metabolism.

Autor: Ichida H; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan., Fukami T; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan. Electronic address: tatsuki@p.kanazawa-u.ac.jp., Kudo T; Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co. Ltd., Kobe, Japan., Mishiro K; Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Japan., Takano S; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan., Nakano M; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan., Morinaga G; Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co. Ltd., Kobe, Japan., Matsui A; Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co. Ltd., Kobe, Japan., Ishiguro N; Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co. Ltd., Kobe, Japan., Nakajima M; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan.
Jazyk: angličtina
Zdroj: Archives of biochemistry and biophysics [Arch Biochem Biophys] 2023 Mar 01; Vol. 736, pp. 109536. Date of Electronic Publication: 2023 Jan 29.
DOI: 10.1016/j.abb.2023.109536
Abstrakt: Nabumetone, a nonsteroidal anti-inflammatory prodrug, is converted to a pharmacologically active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA); however, it is 11-fold more efficiently converted to 4-(6-methoxy-2-naphthyl)butan-2-ol (MNBO) via a reduction reaction in human hepatocytes. The goal of this study was to identify the enzyme(s) responsible for MNBO formation from nabumetone in the human liver. MNBO formation by human liver microsomes (HLM) was 5.7-fold higher than in the liver cytosol. In a panel of 24 individual HLM samples with quantitative proteomics data, the 17β-hydroxysteroid dehydrogenase 12 (HSD17B12) protein level had the high correlation coefficient (r = 0.80, P < 0.001) among 4457 proteins quantified in microsomal fractions during MNBO formation. Recombinant HSD17B12 expressed in HEK293T cells exhibited prominent nabumetone reductase activity, and the contribution of HSD17B12 to the activity in the HLM was calculated as almost 100%. MNBO formation in HepG2 and Huh7 cells was significantly decreased by the knockdown of HSD17B12. We also examined the role of HSD17B12 in drug metabolism and found that recombinant HSD17B12 catalyzed the reduction reactions of pentoxifylline and S-warfarin, suggesting that HSD17B12 prefers compounds containing a methyl ketone group on the alkyl chain. In conclusion, our study demonstrated that HSD17B12 is responsible for the formation of MNBO from nabumetone. Together with the evidence for pentoxifylline and S-warfarin reduction, this is the first study to report that HSD17B12, which is known to metabolize endogenous compounds, such as estrone and 3-ketoacyl-CoA, plays a role as a drug-metabolizing enzyme.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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