AKR1C4 explained

Aldo-keto reductase family 1 member C4, also known as 3α-Hydroxysteroid dehydrogenase type 1 (3α-HSD1),^{[1] [2] [3]} is an enzyme that in humans is encoded by the AKR1C4 gene.^{[4] [5] [6]} It is known to be necessary for the synthesis of the endogenous neurosteroids allopregnanolone, tetrahydrodeoxycorticosterone, and 3α-androstanediol. It is also known to catalyze the reversible conversion of 3α-androstanediol (5α-androstane-3α,17β-diol) to dihydrotestosterone (DHT, 5α-androstan-17β-ol-3-one) and vice versa.^[7]

Function

This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the bioreduction of chlordecone, a toxic organochlorine pesticide, to chlordecone alcohol in liver. This gene shares high sequence identity with three other gene members and is clustered with those three genes at 10p15-p14 on chromosome 10.^[6]

Clinical significance

Various antidepressants, including the SSRIs fluoxetine, fluvoxamine, sertraline, and paroxetine, the SNRI venlafaxine, and mirtazapine, have been found to activate certain isoforms of the 3α-hydroxysteroid dehydrogenase, resulting in a selective facilitation of 5α-dihydroprogesterone conversion into allopregnanolone. This action has been implicated in their effectiveness in affective disorders, and has resulted in them being described as selective brain steroidogenic stimulants (SBSSs).^{[8] [9] [10]}

See also

• Steroidogenic enzyme
• 3α-Hydroxysteroid dehydrogenase
• 3β-hydroxysteroid dehydrogenase

References

Further reading

• Binstock JM, Iyer RB, Hamby CV, Fried VA, Schwartz IS, Weinstein BI, Southren AL . Human hepatic 3 alpha-hydroxysteroid dehydrogenase: possible identity with human hepatic chlordecone reductase . Biochemical and Biophysical Research Communications . 187 . 2 . 760–6 . September 1992 . 1530633 . 10.1016/0006-291X(92)91260-W .
• Winters CJ, Molowa DT, Guzelian PS . Isolation and characterization of cloned cDNAs encoding human liver chlordecone reductase . Biochemistry . 29 . 4 . 1080–7 . January 1990 . 2187532 . 10.1021/bi00456a034 .
• Khanna M, Qin KN, Cheng KC . Distribution of 3 alpha-hydroxysteroid dehydrogenase in rat brain and molecular cloning of multiple cDNAs encoding structurally related proteins in humans . The Journal of Steroid Biochemistry and Molecular Biology . 53 . 1–6 . 41–6 . June 1995 . 7626489 . 10.1016/0960-0760(95)00019-V . 11316547 . free .
• Khanna M, Qin KN, Wang RW, Cheng KC . Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases . The Journal of Biological Chemistry . 270 . 34 . 20162–8 . August 1995 . 7650035 . 10.1074/jbc.270.34.20162 . free .
• Deyashiki Y, Ogasawara A, Nakayama T, Nakanishi M, Miyabe Y, Sato K, Hara A . Molecular cloning of two human liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical with chlordecone reductase and bile-acid binder . The Biochemical Journal . 299 (Pt 2) . 2 . 545–52 . April 1994 . 8172617 . 1138306 . 10.1042/bj2990545 .
• Qin KN, New MI, Cheng KC . Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase . The Journal of Steroid Biochemistry and Molecular Biology . 46 . 6 . 673–9 . December 1993 . 8274401 . 10.1016/0960-0760(93)90308-J . 36210133 .
• Kume T, Iwasa H, Shiraishi H, Yokoi T, Nagashima K, Otsuka M, Terada T, Takagi T, Hara A, Kamataki T . Characterization of a novel variant (S145C/L311V) of 3alpha-hydroxysteroid/dihydrodiol dehydrogenase in human liver . Pharmacogenetics . 9 . 6 . 763–71 . December 1999 . 10634139 . 10.1097/00008571-199912000-00011 .
• Nishizawa M, Nakajima T, Yasuda K, Kanzaki H, Sasaguri Y, Watanabe K, Ito S . Close kinship of human 20alpha-hydroxysteroid dehydrogenase gene with three aldo-keto reductase genes . Genes to Cells . 5 . 2 . 111–25 . February 2000 . 10672042 . 10.1046/j.1365-2443.2000.00310.x . 25136637 . free .
• Dufort I, Labrie F, Luu-The V . Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: differential lability and tissue distribution . The Journal of Clinical Endocrinology and Metabolism . 86 . 2 . 841–6 . February 2001 . 10.1210/jcem.86.2.7216 . 11158055 . free .
• Ozeki T, Takahashi Y, Kume T, Nakayama K, Yokoi T, Nunoya K, Hara A, Kamataki T . Co-operative regulation of the transcription of human dihydrodiol dehydrogenase (DD)4/aldo-keto reductase (AKR)1C4 gene by hepatocyte nuclear factor (HNF)-4alpha/gamma and HNF-1alpha . The Biochemical Journal . 355 . Pt 2 . 537–44 . April 2001 . 11284743 . 1221767 . 10.1042/0264-6021:3550537 .
• Ozeki T, Takahashi Y, Nakayama K, Kamataki T . Hepatocyte nuclear factor (HNF)-4 alpha/gamma, HNF-1 alpha, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene . Archives of Biochemistry and Biophysics . 405 . 2 . 185–90 . September 2002 . 12220531 . 10.1016/S0003-9861(02)00384-3 .
• Ozeki T, Takahashi Y, Nakayama K, Funayama M, Nagashima K, Kodama T, Kamataki T . Hepatocyte nuclear factor-4 alpha/gamma and hepatocyte nuclear factor-1 alpha as causal factors of interindividual difference in the expression of human dihydrodiol dehydrogenase 4 mRNA in human livers . Pharmacogenetics . 13 . 1 . 49–53 . January 2003 . 12544512 . 10.1097/00008571-200301000-00007 .
• Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, Pasini A, Schwarz M, Kempter H, Rupprecht R . Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity . Molecular Psychiatry . 11 . 3 . 261–72 . March 2006 . 16344854 . 10.1038/sj.mp.4001782 . 21473462 .

Notes and References

1. Li . Tang . Zhang . Wenfa . Lin . Sheng-Xiang . Steroid enzyme and receptor expression and regulations in breast tumor samples – A statistical evaluation of public data . The Journal of Steroid Biochemistry and Molecular Biology . February 2020 . 196 . 105494 . 10.1016/j.jsbmb.2019.105494 . 31610224 .
2. Longone . Patrizia . Rupprecht . Rainer . Manieri . Gaia A. . Bernardi . Giorgio . Romeo . Elena . Pasini . Augusto . The complex roles of neurosteroids in depression and anxiety disorders . Neurochemistry International . March 2008 . 52 . 4–5 . 596–601 . 10.1016/j.neuint.2007.10.001 . 17996986 .
3. Savchuk . I. . Morvan . M.L. . Antignac . J.P. . Gemzell-Danielsson . K. . Le Bizec . B. . Söder . O. . Svechnikov . K. . The human genital tubercle is steroidogenic organ at early pregnancy . Molecular and Cellular Endocrinology . December 2018 . 477 . 148–155 . 10.1016/j.mce.2018.06.012 . 29928928 .
4. 10.15347/WJM/2023.003 . free . Alternative androgen pathways . 3 April 2023 . Masiutin MM, Yadav MK . WikiJournal of Medicine . 10 . 29 . 257943362 .
5. Khanna M, Qin KN, Klisak I, Belkin S, Sparkes RS, Cheng KC . Localization of multiple human dihydrodiol dehydrogenase (DDH1 and DDH2) and chlordecone reductase (CHDR) genes in chromosome 10 by the polymerase chain reaction and fluorescence in situ hybridization . Genomics . 25 . 2 . 588–90 . January 1995 . 7789999 . 10.1016/0888-7543(95)80066-U . free .
6. AKR1C4 aldo-keto reductase family 1 member C4 [Homo sapiens (human) ]
7. Rizner TL, Lin HK, Peehl DM, Steckelbroeck S, Bauman DR, Penning TM . Human type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2) and androgen metabolism in prostate cells . Endocrinology . 144 . 7 . 2922–32 . July 2003 . 12810547 . 10.1210/en.2002-0032 . free .
8. Griffin LD, Mellon SH . Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes . Proceedings of the National Academy of Sciences of the United States of America . 96 . 23 . 13512–7 . November 1999 . 10557352 . 23979 . 10.1073/pnas.96.23.13512 . 1999PNAS...9613512G . free .
9. Pinna G . In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis . Behavioural Pharmacology . 21 . 5–6 . 438–50 . September 2010 . 20716970 . 2942072 . 10.1097/FBP.0b013e32833d8ba0 .
10. Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, Pasini A, Schwarz M, Kempter H, Rupprecht R . Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity . Molecular Psychiatry . 11 . 3 . 261–72 . March 2006 . 16344854 . 10.1038/sj.mp.4001782 . 21473462 .