Involvement of porcine and human carbonyl reductases in the metabolism of epiandrosterone, 11-oxygenated steroids, neurosteroids, and corticosteroids.

Autor: Endo S; The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1194, Japan; Center for One Medicine Innovative Translational Research, Gifu University, Gifu 501-1193, Japan. Electronic address: endou.satoshi.n1@f.gifu-u.ac.jp., Morikawa Y; Forensic Science Laboratory, Gifu Prefectural Police Headquarters, Gifu 500-8501, Japan., Suenami K; Forensic Science Laboratory, Gifu Prefectural Police Headquarters, Gifu 500-8501, Japan., Sakai Y; Forensic Science Laboratory, Gifu Prefectural Police Headquarters, Gifu 500-8501, Japan., Abe N; Laboratory of Pharmacognosy, Gifu Pharmaceutical University, Gifu 501-1196, Japan., Matsunaga T; Laboratory of Bioinformatics, Gifu Pharmaceutical University, Gifu 502-8585, Japan., Hara A; Faculty of Engineering, Gifu University, Gifu 501-1193, Japan., Takasu M; Center for One Medicine Innovative Translational Research, Gifu University, Gifu 501-1193, Japan; Institute for Advanced Study, Gifu University, Gifu 501-1193, Japan.
Jazyk: angličtina
Zdroj: The Journal of steroid biochemistry and molecular biology [J Steroid Biochem Mol Biol] 2024 Oct; Vol. 243, pp. 106574. Date of Electronic Publication: 2024 Jun 28.
DOI: 10.1016/j.jsbmb.2024.106574
Abstrakt: Porcine carbonyl reductases (pCBR1 and pCBR-N1) and aldo-keto reductases (pAKR1C1 and pAKR1C4) exhibit hydroxysteroid dehydrogenase (HSD) activity. However, their roles in the metabolism of porcine-specific androgens (19-nortestosterone and epiandrosterone), 11-oxygenated androgens, neurosteroids, and corticosteroids remain unclear. Here, we compared the steroid specificity of the four recombinant enzymes by kinetic and product analyses. In C 18 /C 19 -steroids,11-keto- and 11β-hydroxy-5α-androstane-3,17-diones were reduced by all the enzymes, whereas 5α-dihydronandrolone (19-nortestosterone metabolite) and 11-ketodihydrotestosterone were reduced by pCBR1, pCBR-N1, and pAKR1C1, of which pCBR1 exhibited the lowest (submicromolar) K m values. Product analysis showed that pCBR1 and pCBR-N1 function as 3α/β-HSDs, in contrast to pAKR1C1 and pAKR1C4 (acting as 3β-HSD and 3α-HSD, respectively). Additionally, 17β-HSD activity was observed in pCBR1 and pCBR-N1 (toward epiandrosterone and its 11-oxygenated derivatives) and in pAKR1C1 (toward androsterone, 4-androstene-3,17-dione and their 11-oxygenated derivatives). The four enzymes also showed different substrate specificity for 3-keto-5α/β-dihydro-C 21 -steroids, including GABAergic neurosteroid precursors and corticosteroid metabolites. 5β-Dihydroprogesterone was reduced by all the enzymes, whereas 5α-dihydroprogesterone was reduced only by pCBR1, and 5α/β-dihydrodeoxycorticosterones by pCBR1 and pCBR-N1. The two pCBRs also reduced the 5α/β-dihydro-metabolites of cortisol, 11-deoxycortisol, cortisone, and corticosterone. pCBR1 exhibited lower K m values (0.3-2.9 μM) for the 3-keto-C 21 -steroids than pCBR-N1 (K m =10-36 μM). The reduced products of the 3-keto-C 21 -steroids by pCBR1 and pCBR-N1 were their 3α-hydroxy-metabolites. Finally, we found that human CBR1 has similar substrate specificity for the C 18 /C 19 /C 21 -steroids to pCBR-N1. Based on these results, it was concluded that porcine and human CBRs can be involved in the metabolism of the aforementioned steroids as 3α/β,17β-HSDs.
Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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