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Gene Review

AKR1C1  -  aldo-keto reductase family 1, member C1

Homo sapiens

Synonyms: 2-ALPHA-HSD, 20-ALPHA-HSD, 20-alpha-HSD, 20-alpha-hydroxysteroid dehydrogenase, Aldo-keto reductase family 1 member C1, ...
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Disease relevance of AKR1C1

  • Immunohistochemical staining confirmed loss of AKR1C1 expression in breast tumors [1].
  • RNase protection assays identified AKR1C1 (DD1) mRNA as the transcript which was up-regulated by mono- and bi-functional inducers and ROS in both human hepatoma (HepG2) and colon carcinoma (HT29) cells [2].
  • It is suggested that the expression of AKR1C1 and AKR1C3 in endometrial cancer will govern the ratio of P:E2 [3].
  • In conclusion, inverse expressions of DDH and GST may be associated with carcinogenesis and disease progression for ESCC patients, but their biological function and pathophysiological regulation in tumors require additional studies [4].
  • We investigated the significances of the expressions of dihydrodiol dehydrogenase (DDH) and glutathione-S-transferase (GST) in patients with esophageal squamous cell carcinoma (ESCC) [4].

Psychiatry related information on AKR1C1


High impact information on AKR1C1

  • Thrombin associated with the platelet membrane presumably formed a C3 convertase that entered the known complement sequence at the C3 stage and proceeded to activate the terminal components through the known sequence to C9 [7].
  • Prostaglandins with a C9 ketooxygen stimulate a bicarbonate-rich choleresis and those with a C9 hydroxyloxygen produce a chloride-rich choleresis [8].
  • Surprisingly, the 5' catalytic domain shares structural homology with RNase H despite the lack of sequence homology and contains an uncommon DDH triad [9].
  • However, (S)-[1,3,4-2H3]norlaudanosoline furnished a good isotopic enrichment and the loss of a single deuterium atom at the C-9 position of the morphine molecule, indicating that the change of configuration from (S)- to (R)-reticuline occurs via the intermediacy of 1,2-dehydroreticuline [10].
  • The C9 methyl group of retinal interacts with glycine-121 in rhodopsin [11].

Chemical compound and disease context of AKR1C1


Biological context of AKR1C1

  • These tissue distribution patterns differ from those of human AKR1C1 and AKR1C4, which are expressed ubiquitously and liver-specific, respectively [15].
  • Of these, AKR1C1 possessed one of the highest specific activities and was the only isoform induced by oxidative stress and by agents that deplete glutathione (ethacrynic acid) [16].
  • The human aldo-keto reductase AKR1C1 (20alpha(3alpha)-hydroxysteroid dehydrogenase) is induced by electrophilic Michael acceptors and reactive oxygen species (ROS) via a presumptive antioxidant response element (Burczynski, M. E., Lin, H. K., and Penning, T. M. (1999) Cancer Res. 59, 607-614) [16].
  • 4-Hydroxy-2-nonenal (HNE) and other alpha,beta-unsaturated aldehydes produced during lipid peroxidation were reduced by AKR1C1 with high catalytic efficiency [16].
  • 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 [17].

Anatomical context of AKR1C1


Associations of AKR1C1 with chemical compounds


Other interactions of AKR1C1

  • Neither AKR1C1 nor AKR1C4 was found to possess high reductase activity towards aliphatic aldehydes, aromatic aldehydes, aldoses or dicarbonyls [18].
  • The AKR1C1 promoter also harbored this same ARE element in a highly homologous region, which was also bound by NRF2 in a ChiP analysis [22].
  • Four human 3alpha-HSD isoforms exist and correspond to AKR1C1-AKR1C4 of the aldo-keto reductase (AKR) superfamily [23].
  • Treatment of the colon cell line with ICZ or SUL caused increases in the levels of mRNA for CYP1A1, AKR1C1, and NQO1 that were consistent with the enzyme data [24].
  • Strict conservation of the intron-exon junctions in the human hepatic DDH and two other members of the monomeric oxidoreductase gene family, aldose reductase and mouse major vas deferens protein suggests evolution from a common ancestral gene [25].

Analytical, diagnostic and therapeutic context of AKR1C1


  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. Isoform-specific induction of a human aldo-keto reductase by polycyclic aromatic hydrocarbons (PAHs), electrophiles, and oxidative stress: implications for the alternative pathway of PAH activation catalyzed by human dihydrodiol dehydrogenase. Burczynski, M.E., Lin, H.K., Penning, T.M. Cancer Res. (1999) [Pubmed]
  3. AKR1C1 and AKR1C3 may determine progesterone and estrogen ratios in endometrial cancer. Rizner, T.L., Smuc, T., Rupreht, R., Sinkovec, J., Penning, T.M. Mol. Cell. Endocrinol. (2006) [Pubmed]
  4. Inverse expression of dihydrodiol dehydrogenase and glutathione-S-transferase in patients with esophageal squamous cell carcinoma. Wang, L.S., Chow, K.C., Wu, Y.C., Lin, T.Y., Li, W.Y. Int. J. Cancer (2004) [Pubmed]
  5. Up-regulated production and activation of the complement system in Alzheimer's disease brain. Yasojima, K., Schwab, C., McGeer, E.G., McGeer, P.L. Am. J. Pathol. (1999) [Pubmed]
  6. Induction of complement C9 messenger RNAs in human neuronal cells by inflammatory stimuli: relevance to neurodegenerative disorders. Klegeris, A., Schwab, C., Bissonnette, C.J., McGeer, P.L. Exp. Gerontol. (2001) [Pubmed]
  7. The human complement system in thrombin-mediated platelet function. Polley, M.J., Nachman, R. J. Exp. Med. (1978) [Pubmed]
  8. Arachidonic acid metabolites in hepatobiliary physiology and disease. Kaminski, D.L. Gastroenterology (1989) [Pubmed]
  9. Structure of the C-terminal half of UvrC reveals an RNase H endonuclease domain with an Argonaute-like catalytic triad. Karakas, E., Truglio, J.J., Croteau, D., Rhau, B., Wang, L., Van Houten, B., Kisker, C. EMBO J. (2007) [Pubmed]
  10. How human neuroblastoma cells make morphine. Boettcher, C., Fellermeier, M., Boettcher, C., Dräger, B., Zenk, M.H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  11. The C9 methyl group of retinal interacts with glycine-121 in rhodopsin. Han, M., Groesbeek, M., Sakmar, T.P., Smith, S.O. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  12. Gene expression profiles of HeLa Cells impacted by hepatitis C virus non-structural protein NS4B. Zheng, Y., Ye, L.B., Liu, J., Jing, W., Timani, K.A., Yang, X.J., Yang, F., Wang, W., Gao, B., Wu, Z.H. J. Biochem. Mol. Biol. (2005) [Pubmed]
  13. Ubiquitous induction of resistance to platinum drugs in human ovarian, cervical, germ-cell and lung carcinoma tumor cells overexpressing isoforms 1 and 2 of dihydrodiol dehydrogenase. Deng, H.B., Adikari, M., Parekh, H.K., Simpkins, H. Cancer Chemother. Pharmacol. (2004) [Pubmed]
  14. C5b-9 terminal complex protects oligodendrocytes from apoptotic cell death by inhibiting caspase-8 processing and up-regulating FLIP. Cudrici, C., Niculescu, F., Jensen, T., Zafranskaia, E., Fosbrink, M., Rus, V., Shin, M.L., Rus, H. J. Immunol. (2006) [Pubmed]
  15. 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]
  16. The reactive oxygen species--and Michael acceptor-inducible human aldo-keto reductase AKR1C1 reduces the alpha,beta-unsaturated aldehyde 4-hydroxy-2-nonenal to 1,4-dihydroxy-2-nonene. Burczynski, M.E., Sridhar, G.R., Palackal, N.T., Penning, T.M. J. Biol. Chem. (2001) [Pubmed]
  17. 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]
  18. 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]
  19. 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]
  20. 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]
  21. 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]
  22. 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]
  23. Structure-function relationships in 3alpha-hydroxysteroid dehydrogenases: a comparison of the rat and human isoforms. Penning, T.M., Jin, Y., Heredia, V.V., Lewis, M. J. Steroid Biochem. Mol. Biol. (2003) [Pubmed]
  24. Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. Bonnesen, C., Eggleston, I.M., Hayes, J.D. Cancer Res. (2001) [Pubmed]
  25. Genomic organization and chromosomal localization of a novel human hepatic dihydrodiol dehydrogenase with high affinity bile acid binding. Lou, H., Hammond, L., Sharma, V., Sparkes, R.S., Lusis, A.J., Stolz, A. J. Biol. Chem. (1994) [Pubmed]
  26. High-affinity stereoselective reduction of the enantiomers of ketotifen and of ketonic nortriptyline metabolites by aldo-keto reductases from human liver. Breyer-Pfaff, U., Nill, K. Biochem. Pharmacol. (2000) [Pubmed]
  27. 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]
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