Logo of biochemjBJ Latest papers and much more!
Biochem J. 2000 Oct 1; 351(Pt 1): 67–77.
PMCID: PMC1221336

Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones.


The kinetic parameters, steroid substrate specificity and identities of reaction products were determined for four homogeneous recombinant human 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) isoforms of the aldo-keto reductase (AKR) superfamily. The enzymes correspond to type 1 3alpha-HSD (AKR1C4), type 2 3alpha(17beta)-HSD (AKR1C3), type 3 3alpha-HSD (AKR1C2) and 20alpha(3alpha)-HSD (AKR1C1), and share at least 84% amino acid sequence identity. All enzymes acted as NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductases and as 3alpha-, 17beta- and 20alpha-hydroxysteroid oxidases. The functional plasticity of these isoforms highlights their ability to modulate the levels of active androgens, oestrogens and progestins. Salient features were that AKR1C4 was the most catalytically efficient, with k(cat)/K(m) values for substrates that exceeded those obtained with other isoforms by 10-30-fold. In the reduction direction, all isoforms inactivated 5alpha-dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one; 5alpha-DHT) to yield 5alpha-androstane-3alpha,17beta-diol (3alpha-androstanediol). However, only AKR1C3 reduced Delta(4)-androstene-3,17-dione to produce significant amounts of testosterone. All isoforms reduced oestrone to 17beta-oestradiol, and progesterone to 20alpha-hydroxy-pregn-4-ene-3,20-dione (20alpha-hydroxyprogesterone). In the oxidation direction, only AKR1C2 converted 3alpha-androstanediol to the active hormone 5alpha-DHT. AKR1C3 and AKR1C4 oxidized testosterone to Delta(4)-androstene-3,17-dione. All isoforms oxidized 17beta-oestradiol to oestrone, and 20alpha-hydroxyprogesterone to progesterone. Discrete tissue distribution of these AKR1C enzymes was observed using isoform-specific reverse transcriptase-PCR. AKR1C4 was virtually liver-specific and its high k(cat)/K(m) allows this enzyme to form 5alpha/5beta-tetrahydrosteroids robustly. AKR1C3 was most prominent in the prostate and mammary glands. The ability of AKR1C3 to interconvert testosterone with Delta(4)-androstene-3,17-dione, but to inactivate 5alpha-DHT, is consistent with this enzyme eliminating active androgens from the prostate. In the mammary gland, AKR1C3 will convert Delta(4)-androstene-3,17-dione to testosterone (a substrate aromatizable to 17beta-oestradiol), oestrone to 17beta-oestradiol, and progesterone to 20alpha-hydroxyprogesterone, and this concerted reductive activity may yield a pro-oesterogenic state. AKR1C3 is also the dominant form in the uterus and is responsible for the synthesis of 3alpha-androstanediol which has been implicated as a parturition hormone. The major isoforms in the brain, capable of synthesizing anxiolytic steroids, are AKR1C1 and AKR1C2. These studies are in stark contrast with those in rat where only a single AKR with positional- and stereo-specificity for 3alpha-hydroxysteroids exists.

Full Text

The Full Text of this article is available as a PDF (268K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • TOMKINS GM. Enzymatic mechanisms of hormone metabolism. I. Oxidation-reduction of the steroid nucleus. Recent Prog Horm Res. 1956;12:125–133. [PubMed]
  • Penning TM, Smithgall TE, Askonas LJ, Sharp RB. Rat liver 3 alpha-hydroxysteroid dehydrogenase. Steroids. 1986 Apr-May;47(4-5):221–247. [PubMed]
  • Hung CF, Penning TM. Members of the nuclear factor 1 transcription factor family regulate rat 3alpha-hydroxysteroid/dihydrodiol dehydrogenase (3alpha-HSD/DD AKR1C9) gene expression: a member of the aldo-keto reductase superfamily. Mol Endocrinol. 1999 Oct;13(10):1704–1717. [PubMed]
  • Danielsson H, Sjövall J. Bile acid metabolism. Annu Rev Biochem. 1975;44:233–253. [PubMed]
  • Liao S, Liang T, Fang S, Castañeda E, Shao TC. Steroid structure and androgenic activity. Specificities involved in the receptor binding and nuclear retention of various androgens. J Biol Chem. 1973 Sep 10;248(17):6154–6162. [PubMed]
  • Taurog JD, Moore RJ, Wilson JD. Partial characterization of the cytosol 3 alpha-hydroxysteroid: NAD(P)+oxidoreductase of rat ventral prostate. Biochemistry. 1975 Feb 25;14(4):810–817. [PubMed]
  • Jacobi GH, Moore RJ, Wilson JD. Characterization of the 3alpha-hydroxysteroid dehydrogenase of dog prostate. J Steroid Biochem. 1977 Jul;8(7):719–723. [PubMed]
  • Jacobi GH, Wilson JD. The formation of 5alpha-androstane-3alpha, 17beta-diol by dog prostate. Endocrinology. 1976 Aug;99(2):602–610. [PubMed]
  • Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science. 1986 May 23;232(4753):1004–1007. [PubMed]
  • Majewska MD. Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol. 1992;38(4):379–395. [PubMed]
  • Lambert JJ, Belelli D, Hill-Venning C, Peters JA. Neurosteroids and GABAA receptor function. Trends Pharmacol Sci. 1995 Sep;16(9):295–303. [PubMed]
  • Morrow AL, VanDoren MJ, Devaud LL. Effects of progesterone or neuroactive steroid? Nature. 1998 Oct 15;395(6703):652–653. [PubMed]
  • Mahendroo MS, Cala KM, Russell DW. 5 alpha-reduced androgens play a key role in murine parturition. Mol Endocrinol. 1996 Apr;10(4):380–392. [PubMed]
  • Mahendroo MS, Porter A, Russell DW, Word RA. The parturition defect in steroid 5alpha-reductase type 1 knockout mice is due to impaired cervical ripening. Mol Endocrinol. 1999 Jun;13(6):981–992. [PubMed]
  • Stolz A, Hammond L, Lou H, Takikawa H, Ronk M, Shively JE. cDNA cloning and expression of the human hepatic bile acid-binding protein. A member of the monomeric reductase gene family. J Biol Chem. 1993 May 15;268(14):10448–10457. [PubMed]
  • Hara A, Matsuura K, Tamada Y, Sato K, Miyabe Y, Deyashiki Y, Ishida N. Relationship of human liver dihydrodiol dehydrogenases to hepatic bile-acid-binding protein and an oxidoreductase of human colon cells. Biochem J. 1996 Jan 15;313(Pt 2):373–376. [PMC free article] [PubMed]
  • 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. Biochem J. 1994 Apr 15;299(Pt 2):545–552. [PMC free article] [PubMed]
  • Khanna M, Qin KN, Wang RW, Cheng KC. Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases. J Biol Chem. 1995 Aug 25;270(34):20162–20168. [PubMed]
  • Lin HK, Jez JM, Schlegel BP, Peehl DM, Pachter JA, Penning TM. Expression and characterization of recombinant type 2 3 alpha-hydroxysteroid dehydrogenase (HSD) from human prostate: demonstration of bifunctional 3 alpha/17 beta-HSD activity and cellular distribution. Mol Endocrinol. 1997 Dec;11(13):1971–1984. [PubMed]
  • Dufort I, Soucy P, Labrie F, Luu-The V. Molecular cloning of human type 3 3 alpha-hydroxysteroid dehydrogenase that differs from 20 alpha-hydroxysteroid dehydrogenase by seven amino acids. Biochem Biophys Res Commun. 1996 Nov 12;228(2):474–479. [PubMed]
  • Jez JM, Flynn TG, Penning TM. A new nomenclature for the aldo-keto reductase superfamily. Biochem Pharmacol. 1997 Sep 15;54(6):639–647. [PubMed]
  • Jez JM, Bennett MJ, Schlegel BP, Lewis M, Penning TM. Comparative anatomy of the aldo-keto reductase superfamily. Biochem J. 1997 Sep 15;326(Pt 3):625–636. [PMC free article] [PubMed]
  • Labrie F, Luu-The V, Lin SX, Labrie C, Simard J, Breton R, Bélanger A. The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology. Steroids. 1997 Jan;62(1):148–158. [PubMed]
  • Dufort I, Rheault P, Huang XF, Soucy P, Luu-The V. Characteristics of a highly labile human type 5 17beta-hydroxysteroid dehydrogenase. Endocrinology. 1999 Feb;140(2):568–574. [PubMed]
  • Griffin LD, Mellon SH. Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13512–13517. [PMC free article] [PubMed]
  • Pawlowski JE, Penning TM. Overexpression and mutagenesis of the cDNA for rat liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase. Role of cysteines and tyrosines in catalysis. J Biol Chem. 1994 May 6;269(18):13502–13510. [PubMed]
  • Ma H, Penning TM. Characterization of homogeneous recombinant rat ovarian 20alpha-hydroxysteroid dehydrogenase: fluorescent properties and inhibition profile. Biochem J. 1999 Aug 1;341(Pt 3):853–859. [PMC free article] [PubMed]
  • Burczynski ME, Harvey RG, Penning TM. Expression and characterization of four recombinant human dihydrodiol dehydrogenase isoforms: oxidation of trans-7, 8-dihydroxy-7,8-dihydrobenzo[a]pyrene to the activated o-quinone metabolite benzo[a]pyrene-7,8-dione. Biochemistry. 1998 May 12;37(19):6781–6790. [PubMed]
  • WILKINSON GN. Statistical estimations in enzyme kinetics. Biochem J. 1961 Aug;80:324–332. [PMC free article] [PubMed]
  • Biswas MG, Russell DW. Expression cloning and characterization of oxidative 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate. J Biol Chem. 1997 Jun 20;272(25):15959–15966. [PubMed]
  • Bennett MJ, Schlegel BP, Jez JM, Penning TM, Lewis M. Structure of 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase complexed with NADP+. Biochemistry. 1996 Aug 20;35(33):10702–10711. [PubMed]
  • Bennett MJ, Albert RH, Jez JM, Ma H, Penning TM, Lewis M. Steroid recognition and regulation of hormone action: crystal structure of testosterone and NADP+ bound to 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase. Structure. 1997 Jun 15;5(6):799–812. [PubMed]
  • Ma H, Penning TM. Conversion of mammalian 3alpha-hydroxysteroid dehydrogenase to 20alpha-hydroxysteroid dehydrogenase using loop chimeras: changing specificity from androgens to progestins. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11161–11166. [PMC free article] [PubMed]
  • 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 Cells. 2000 Feb;5(2):111–125. [PubMed]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...