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Gene Review

AKR1C2  -  aldo-keto reductase family 1, member C2

Homo sapiens

Synonyms: 3-alpha-HSD3, AKR1C-pseudo, Aldo-keto reductase family 1 member C2, BABP, Chlordecone reductase homolog HAKRD, ...
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Disease relevance of AKR1C2


High impact information on AKR1C2

  • Phenyl ketone 1 is a cell-permeable fluorogenic probe that permits a direct, real-time, and operationally simple readout of AKR1C2 enzyme activity in intact mammalian cells [5].
  • The high selectivity of phenyl ketone 1 for AKR1C2 over the many endogenous reductases present in mammalian cells was established by a quantitative comparison of the metabolic rates between null control cells (COS-1) and AKR1C2-transfected cells [5].
  • Fluorogenic metabolic probes for direct activity readout of redox enzymes: Selective measurement of human AKR1C2 in living cells [5].
  • Moreover, treatment of AREc32 cells with BSO immediately before exposure to anticancer drugs enhanced induction of ARE-driven luciferase activity by cisplatin, BCNU, chlorambucil, and melphalan and also induced endogenous AKR1C (AKR1C refers to AKR1C1 and AKR1C2), a target gene of Nrf2 [6].
  • Suppression of AKR1C1 alone or with AKR1C2 in T-47D cells led to decreased growth in the presence of progesterone [1].

Chemical compound and disease context of AKR1C2

  • Role of human type 3 3alpha-hydroxysteroid dehydrogenase (AKR1C2) in androgen metabolism of prostate cancer cells [7].
  • In androgen dependent human prostate cancer cells LNCaP, it was not possible to ascertain the preferred direction of AKR1C2 by stable transfection due to the high rate of 5alpha-DHT and 3alpha-diol glucuronidation [7].
  • OBJECTIVES: The aim of the present study was to investigate the association between the homozygous DD (deletion) genotype of the angiotensin-converting enzyme gene and survival and cardiac function in patients with idiopathic congestive heart failure [8].
  • The cytotoxicity of several PAH o-quinones derived from this reaction [naphthalene-1,2-dione (NPQ), benzo[a]pyrene-7,8-dione (BPQ), and 7,12-dimethylbenz[a]anthracene-3,4-dione (DMBAQ)] was examined in rat (H-4IIe) and human (Hep-G2) hepatoma cells which are known to express DD [9].
  • Retention factors on the immobilized artificial membrane column (IAM PC DD 2) with 10% (v/v) methanol-water as mobile phase are able to estimate non-specific toxicity to the fathead minnow with a standard error (SE) of 0.22 log units and coefficient of determination (r2) of 0.97 for 31 compounds [10].

Biological context of AKR1C2


Anatomical context of AKR1C2


Associations of AKR1C2 with chemical compounds


Enzymatic interactions of AKR1C2

  • In mammalian transfection studies all enzymes except AKR1C2 oxidized 3alpha-diol back to DHT where RODH 5, RODH 4, and RL-HSD were the most efficient [19].

Regulatory relationships of AKR1C2


Other interactions of AKR1C2

  • Promoter activities of the 20alpha-HSD, BABP and PGFS genes were high, both in ovarian granulosa cells and hepatocytes [20].
  • Using NAD+, the 3-hydroxymetabolites were efficiently oxidized by homogeneous recombinant AKR1C2 and AKR1C4 [17].
  • Whereas AKR1C2 acted as a 3alpha-HSD toward 5alpha-DHT, it functioned exclusively as a 3beta-HSD on tibolone [17].
  • To determine whether AKR1C2 preferentially functions as a reductase or an oxidase in a cellular context, we transiently transfected AKR1C2 (pcDNA3-AKR1C2) into COS-1 cells and stably transfected pcDNA3-AKR1C2 and pLNCX-AKR1C2 constructs into PC-3 and LNCaP cells, respectively [7].
  • RT-PCR analysis demonstrated the expression of 5 alpha-reductase type 1, 5 beta-reductase, aldo-keto-reductase (AKR) 1C1, AKR1C2, AKR1C3, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) type 2, and 17 alpha-hydroxylase/17,20-lyase (P450c17) [21].

Analytical, diagnostic and therapeutic context of AKR1C2

  • To determine why AKR1C2 has a much lower k(cat) than AKR1C9, the events associated with the binding of cofactor to both enzymes were studied by steady state fluorescence titration and stopped-flow experiments [22].
  • These cells lysates were prepared to examine AKR1C2 expression by Western blot [4].
  • Total RNA was extracted from these cells to analyze the change of AKR1C2 mRNA by Northern blot [4].
  • In the present study we performed site-directed mutagenesis of the seven residues (Thr-38, Arg-47, Leu-54, Cys-87, Val-151, Arg-170 and Gln-172) of DD1 to the corresponding residues (Val, His, Val, Ser, Met, His and Leu respectively) of DD2 [23].
  • Increased expression of the potential proapoptotic molecule DD2 and increased synthesis of leukotriene B4 during allograft rejection in a marine sponge [24].


  1. Selective loss of AKR1C1 and AKR1C2 in breast cancer and their potential effect on progesterone signaling. Ji, Q., Aoyama, C., Nien, Y.D., Liu, P.I., Chen, P.K., Chang, L., Stanczyk, F.Z., Stolz, A. Cancer Res. (2004) [Pubmed]
  2. Selective reduction of AKR1C2 in prostate cancer and its role in DHT metabolism. Ji, Q., Chang, L., VanDenBerg, D., Stanczyk, F.Z., Stolz, A. Prostate (2003) [Pubmed]
  3. Overexpression of aldo-keto reductase 1C2 as a high-risk factor in bladder cancer. Tai, H.L., Lin, T.S., Huang, H.H., Lin, T.Y., Chou, M.C., Chiou, S.H., Chow, K.C. Oncol. Rep. (2007) [Pubmed]
  4. Growth factor NUN increased AKR1C2 expression by activated CDK2 related RB signal transduction pathway in human liver cancer cell line. Lu, D.D. Hepatogastroenterology (2005) [Pubmed]
  5. Fluorogenic metabolic probes for direct activity readout of redox enzymes: Selective measurement of human AKR1C2 in living cells. Yee, D.J., Balsanek, V., Bauman, D.R., Penning, T.M., Sames, D. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  6. Generation of a stable antioxidant response element-driven reporter gene cell line and its use to show redox-dependent activation of nrf2 by cancer chemotherapeutic agents. Wang, X.J., Hayes, J.D., Wolf, C.R. Cancer Res. (2006) [Pubmed]
  7. Role of human type 3 3alpha-hydroxysteroid dehydrogenase (AKR1C2) in androgen metabolism of prostate cancer cells. Rizner, T.L., Lin, H.K., Penning, T.M. Chem. Biol. Interact. (2003) [Pubmed]
  8. The DD genotype of the angiotensin-converting enzyme gene is associated with increased mortality in idiopathic heart failure. Andersson, B., Sylvén, C. J. Am. Coll. Cardiol. (1996) [Pubmed]
  9. Cytotoxicity of polycyclic aromatic hydrocarbon o-quinones in rat and human hepatoma cells. Flowers-Geary, L., Harvey, R.G., Penning, T.M. Chem. Res. Toxicol. (1993) [Pubmed]
  10. Systematic search for surrogate chromatographic models of biopartitioning processes. Cimpean, D.M., Poole, C.F. The Analyst. (2002) [Pubmed]
  11. Sequence of the cDNA of a human dihydrodiol dehydrogenase isoform (AKR1C2) and tissue distribution of its mRNA. Shiraishi, H., Ishikura, S., Matsuura, K., Deyashiki, Y., Ninomiya, M., Sakai, S., Hara, A. Biochem. J. (1998) [Pubmed]
  12. Genomic structure of rat 3alpha-hydroxysteroid/dihydrodiol dehydrogenase (3alpha-HSD/DD, AKR1C9). Lin, H.K., Hung, C.F., Moore, M., Penning, T.M. J. Steroid Biochem. Mol. Biol. (1999) [Pubmed]
  13. Induction of AKR1C2 by phase II inducers: identification of a distal consensus antioxidant response element regulated by NRF2. Lou, H., Du, S., Ji, Q., Stolz, A. Mol. Pharmacol. (2006) [Pubmed]
  14. Altered expression of 3 alpha-hydroxysteroid dehydrogenases in human glaucomatous optic nerve head astrocytes. Agapova, O.A., Yang, P., Wang, W.H., Lane, D.A., Clark, A.F., Weinstein, B.I., Hernandez, M.R. Neurobiol. Dis. (2003) [Pubmed]
  15. Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men. Blouin, K., Richard, C., Brochu, G., Hould, F.S., Lebel, S., Marceau, S., Biron, S., Luu-The, V., Tchernof, A. J. Endocrinol. (2006) [Pubmed]
  16. Structure-function of human 3 alpha-hydroxysteroid dehydrogenases: genes and proteins. Penning, T.M., Jin, Y., Steckelbroeck, S., Lanisnik Rizner, T., Lewis, M. Mol. Cell. Endocrinol. (2004) [Pubmed]
  17. Tibolone is metabolized by the 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo-keto reductase 1C subfamily: inversion of stereospecificity with a delta5(10)-3-ketosteroid. Steckelbroeck, S., Jin, Y., Oyesanmi, B., Kloosterboer, H.J., Penning, T.M. Mol. Pharmacol. (2004) [Pubmed]
  18. Multiple steps determine the overall rate of the reduction of 5alpha-dihydrotestosterone catalyzed by human type 3 3alpha-hydroxysteroid dehydrogenase: implications for the elimination of androgens. Jin, Y., Penning, T.M. Biochemistry (2006) [Pubmed]
  19. Identification of the major oxidative 3alpha-hydroxysteroid dehydrogenase in human prostate that converts 5alpha-androstane-3alpha,17beta-diol to 5alpha-dihydrotestosterone: a potential therapeutic target for androgen-dependent disease. Bauman, D.R., Steckelbroeck, S., Williams, M.V., Peehl, D.M., Penning, T.M. Mol. Endocrinol. (2006) [Pubmed]
  20. Close kinship of human 20alpha-hydroxysteroid dehydrogenase gene with three aldo-keto reductase genes. Nishizawa, M., Nakajima, T., Yasuda, K., Kanzaki, H., Sasaguri, Y., Watanabe, K., Ito, S. Genes Cells (2000) [Pubmed]
  21. The human kidney is a progesterone-metabolizing and androgen-producing organ. Quinkler, M., Bumke-Vogt, C., Meyer, B., Bähr, V., Oelkers, W., Diederich, S. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  22. Examination of the differences in structure-function of human and rat 3alpha-hydroxysteroid dehydrogenase. Jin, Y., Cooper, W.C., Penning, T.M. Chem. Biol. Interact. (2003) [Pubmed]
  23. Identification of amino acid residues responsible for differences in substrate specificity and inhibitor sensitivity between two human liver dihydrodiol dehydrogenase isoenzymes by site-directed mutagenesis. Matsuura, K., Deyashiki, Y., Sato, K., Ishida, N., Miwa, G., Hara, A. Biochem. J. (1997) [Pubmed]
  24. Increased expression of the potential proapoptotic molecule DD2 and increased synthesis of leukotriene B4 during allograft rejection in a marine sponge. Wiens, M., Krasko, A., Blumbach, B., Müller, I.M., Müller, W.E. Cell Death Differ. (2000) [Pubmed]
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