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Gene Review

AKR1C4  -  aldo-keto reductase family 1, member C4

Homo sapiens

Synonyms: 3-alpha-HSD, 3-alpha-HSD1, 3-alpha-hydroxysteroid dehydrogenase type I, Aldo-keto reductase family 1 member C4, C11, ...
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Disease relevance of AKR1C4

  • The luciferase activity was detectable in HepG2 cells but not in human renal adenocarcinoma ACHN cells transfected with the pDD4 Foot A+B: -95/+28, which do not express DD4 mRNA [1].
  • The aim of the present study was to investigate the mRNA expression of 5 alpha-reductase 1 as well as 3 alpha-HSD 1, 2, 3 and 20 alpha-HSD in brain tissue from patients with pharmacoresistant temporal lobe epilepsy (TLE) [2].
  • We have examined phosphatidylinositol turnover and C-kinase distribution in a flat cellular ras-resistant cell line (C11) derived from Kirsten murine sarcoma virus (Ki-MSV) transformed NIH/3T3 cells (DT) [3].
  • The broad substrate specificities of the characterized 3 alpha-HSD enzymes lead to the conclusion that they might participate in the intestinal bioactivation or inactivation of hormones, bile acids and xenobiotics since Comamonas testosteroni and related species are found in the intestinal tract of vertebrates including man [4].
  • Proteins similar to the 3 alpha-HSD were detected and characterized from Comamonas testosteroni strain ATCC 17454 and from a commercially available steroid-induced extract of a patent Pseudomonas strain [4].

Psychiatry related information on AKR1C4


High impact information on AKR1C4

  • Prostaglandin (PG) D2, the predominant prostanoid released from activated mast cells in humans is initially metabolized by reduction of the C-11 keto function to yield 9 alpha,11 beta-PGF2 [6].
  • The remaining 9.5 kb represented the 5'-flanking region of the rat 3 alpha-HSD/DD gene [7].
  • Four human cytosolic aldo-keto reductases (AKR1C1-AKR1C4) are known to act as non-positional-specific 3alpha-/17beta-/20alpha-HSDs [8].
  • Using cDNA microarray, we identified a clone, DD4, that contains the cDNA of a novel gene, spurt (secretory protein in upper respiratory tracts) that was significantly induced by all-trans-retinoic acid in primary cultured human tracheobroncheal epithelia [9].
  • Significant amino acid sequence homology was found with the human chlordecone reductase, bovine prostaglandin F synthetase, and rat hepatic-3 alpha-HSD suggesting, that HBAB is also a member of the recently identified, monomeric oxidoreductase gene family [10].

Chemical compound and disease context of AKR1C4

  • The DD4 cDNA was expressed in Escherichia coli to characterize Ca(2+)-binding of the encoded protein, and Ca(2+) was found to bind to a central segment of 186 amino acids [11].

Biological context of AKR1C4

  • No aberrant expression of AKR1C4 expression or significant differences in SRD5A2 gene expression were found [12].
  • These tissue distribution patterns differ from those of human AKR1C1 and AKR1C4, which are expressed ubiquitously and liver-specific, respectively [13].
  • We have raised polyclonal antibodies that cross-reacted with the two enzymes and isolated two 1.2 kb cDNA clones (C9 and C11) for the two enzymes from a human liver cDNA library using the antibodies [14].
  • We found no clear relationship between the genotypes of DD4 and HNF genes and the expression levels of DD4 mRNA in the subjects [15].
  • A computer-based comparison of the cDNAs of the isoenzymes with the DNA sequence database revealed that the nucleotide and amino acid sequences of DD2 and DD4 are virtually identical with those of human bile-acid binder and human chlordecone reductase cDNAs respectively [14].

Anatomical context of AKR1C4

  • The AKR1C family members proved not to be as widely expressed as the other reductases, with AKR1C1 being observed in only kidney, liver and testis, and AKR1C4 being found in liver alone [16].
  • In primary hepatocytes (which express AKR1C1-AKR1C4), time-dependent reduction of tibolone into 3beta- and 3alpha-hydroxytibolone was observed again in a 4:1 ratio [17].
  • This cDNA showed differences of one, two, four and five nucleotides from the previously reported four cDNA species for a dehydrogenase of human colon carcinoma HT29 cells, human prostatic 3alpha-hydroxysteroid dehydrogenase, a human liver 3alpha-hydroxysteroid dehydrogenase-like protein and chlordecone reductase-like protein respectively [18].
  • The mRNA for DD1 was detected only in liver, kidney, intestine and adrenal gland among Japanese monkey tissues, and that for DD4 was expressed in liver and kidney [13].
  • RNA expression analysis indicates that human type 1 3 alpha-HSD is expressed exclusively in the liver, whereas type 3 is more widely expressed and is found in the liver, adrenal, testis, brain, prostate, and HaCaT keratinocytes [19].

Associations of AKR1C4 with chemical compounds


Other interactions of AKR1C4


Analytical, diagnostic and therapeutic context of AKR1C4

  • Molecular cloning of two human liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical with chlordecone reductase and bile-acid binder [14].
  • A reverse phase HPLC radiochemical assay demonstrated that all four isoforms oxidize (+/-)-BP-diol in the following rank order: DD2 > DD1 > DD4 > DDX [22].
  • Northern blot analysis of RNA from human, gerbil, rabbit, hamster, mouse, and rat livers disclosed hybridization with CDR cDNA only for the first three species.(ABSTRACT TRUNCATED AT 250 WORDS)[23]
  • The binding of sulphobromophthalein to DD4 was instantaneous and reversible, and was detected by fluorescence and ultrafiltration assays [24].
  • Southern blot analysis of human genomic DNA displayed between 45 and 65 kilobases of DNA hybridizable to CDR cDNA and demonstrated several restriction fragment length polymorphisms among 26 individuals [23].


  1. 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. Ozeki, T., Takahashi, Y., Nakayama, K., Kamataki, T. Arch. Biochem. Biophys. (2002) [Pubmed]
  2. Allopregnanolone serum levels and expression of 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase isoforms in hippocampal and temporal cortex of patients with epilepsy. Stoffel-Wagner, B., Watzka, M., Steckelbroeck, S., Ludwig, M., Clusmann, H., Bidlingmaier, F., Casarosa, E., Luisi, S., Elger, C.E., Beyenburg, S. Epilepsy Res. (2003) [Pubmed]
  3. Reduced protein kinase C activity in a ras-resistant cell line derived from Ki-MSV transformed cells. Kamata, T., Sullivan, N.F., Wooten, M.W. Oncogene (1987) [Pubmed]
  4. Characterization of a 3 alpha-hydroxysteroid dehydrogenase/carbonyl reductase from the gram-negative bacterium Comamonas testosteroni. Oppermann, U.C., Maser, E. Eur. J. Biochem. (1996) [Pubmed]
  5. Polymorphisms in genes involved in estrogen and progesterone metabolism and mammographic density changes in women randomized to postmenopausal hormone therapy: results from a pilot study. Lord, S.J., Mack, W.J., Van Den Berg, D., Pike, M.C., Ingles, S.A., Haiman, C.A., Wang, W., Parisky, Y.R., Hodis, H.N., Ursin, G. Breast Cancer Res. (2005) [Pubmed]
  6. 9 alpha,11 beta-prostaglandin F2, a novel metabolite of prostaglandin D2 is a potent contractile agonist of human and guinea pig airways. Beasley, C.R., Robinson, C., Featherstone, R.L., Varley, J.G., Hardy, C.C., Church, M.K., Holgate, S.T. J. Clin. Invest. (1987) [Pubmed]
  7. Cloning, sequencing, and functional analysis of the 5'-flanking region of the rat 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase gene. Lin, H.K., Penning, T.M. Cancer Res. (1995) [Pubmed]
  8. Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the aldo-keto reductase superfamily display significant 3beta-hydroxysteroid dehydrogenase activity: implications for steroid hormone metabolism and action. Steckelbroeck, S., Jin, Y., Gopishetty, S., Oyesanmi, B., Penning, T.M. J. Biol. Chem. (2004) [Pubmed]
  9. Molecular cloning and characterization of spurt, a human novel gene that is retinoic acid-inducible and encodes a secretory protein specific in upper respiratory tracts. Di, Y.P., Harper, R., Zhao, Y., Pahlavan, N., Finkbeiner, W., Wu, R. J. Biol. Chem. (2003) [Pubmed]
  10. cDNA cloning and expression of the human hepatic bile acid-binding protein. A member of the monomeric reductase gene family. Stolz, A., Hammond, L., Lou, H., Takikawa, H., Ronk, M., Shively, J.E. J. Biol. Chem. (1993) [Pubmed]
  11. Molecular cloning of the crustacean DD4 cDNA encoding a Ca(2+)-binding protein. Endo, H., Persson, P., Watanabe, T. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  12. 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]
  13. Molecular characterization of two monkey dihydrodiol dehydrogenases. Higaki, Y., Kamiya, T., Usami, N., Shintani, S., Shiraishi, H., Ishikura, S., Yamamoto, I., Hara, A. Drug Metab. Pharmacokinet. (2002) [Pubmed]
  14. Molecular cloning of two human liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical with chlordecone reductase and bile-acid binder. Deyashiki, Y., Ogasawara, A., Nakayama, T., Nakanishi, M., Miyabe, Y., Sato, K., Hara, A. Biochem. J. (1994) [Pubmed]
  15. 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. Ozeki, T., Takahashi, Y., Nakayama, K., Funayama, M., Nagashima, K., Kodama, T., Kamataki, T. Pharmacogenetics (2003) [Pubmed]
  16. Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members. O'connor, T., Ireland, L.S., Harrison, D.J., Hayes, J.D. Biochem. J. (1999) [Pubmed]
  17. Tibolone metabolism in human liver is catalyzed by 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four isoforms of the aldo-keto reductase (AKR)1C subfamily. Steckelbroeck, S., Oyesanmi, B., Jin, Y., Lee, S.H., Kloosterboer, H.J., Penning, T.M. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  18. 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]
  19. Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: differential lability and tissue distribution. Dufort, I., Labrie, F., Luu-The, V. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  20. Purification and characterization of oxidoreductases-catalyzing carbonyl reduction of the tobacco-specific nitrosamine 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) in human liver cytosol. Atalla, A., Breyer-Pfaff, U., Maser, E. Xenobiotica (2000) [Pubmed]
  21. 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. Penning, T.M., Burczynski, M.E., Jez, J.M., Hung, C.F., Lin, H.K., Ma, H., Moore, M., Palackal, N., Ratnam, K. Biochem. J. (2000) [Pubmed]
  22. 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. Burczynski, M.E., Harvey, R.G., Penning, T.M. Biochemistry (1998) [Pubmed]
  23. Isolation and characterization of cloned cDNAs encoding human liver chlordecone reductase. Winters, C.J., Molowa, D.T., Guzelian, P.S. Biochemistry (1990) [Pubmed]
  24. Activation of human liver 3 alpha-hydroxysteroid dehydrogenase by sulphobromophthalein. Matsuura, K., Tamada, Y., Deyashiki, Y., Miyabe, Y., Nakanishi, M., Ohya, I., Hara, A. Biochem. J. (1996) [Pubmed]
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