Human Cytosolic 3α-Hydroxysteroid Dehydrogenases of the Aldo-keto Reductase Superfamily Display Significant 3β-Hydroxysteroid Dehydrogenase Activity
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The source of NADPH-dependent cytosolic 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity is unknown to date. This important reaction leads e.g. to the reduction of the potent androgen 5alpha-dihydrotestosterone (DHT) into inactive 3beta-androstanediol (3beta-Diol). Four human cytosolic aldo-keto reductases (AKR1C1-AKR1C4) are known to act as non-positional-specific 3alpha-/17beta-/20alpha-HSDs. We now demonstrate that AKR1Cs catalyze the reduction of DHT into both 3alpha- and 3beta-Diol (established by (1)H NMR spectroscopy). The rates of 3alpha- versus 3beta-Diol formation varied significantly among the isoforms, but with each enzyme both activities were equally inhibited by the nonsteroidal anti-inflammatory drug flufenamic acid. In vitro, AKR1Cs also expressed substantial 3alpha[17beta]-hydroxysteroid oxidase activity with 3alpha-Diol as the substrate. However, in contrast to the 3-ketosteroid reductase activity of the enzymes, their hydroxysteroid oxidase activity was potently inhibited by low micromolar concentrations of the opposing cofactor (NADPH). This indicates that in vivo all AKR1Cs will preferentially work as reductases. Human hepatoma (HepG2) cells (which lack 3beta-HSD/Delta(5-4) ketosteroid isomerase mRNA expression, but express AKR1C1-AKR1C3) were able to convert DHT into 3alpha- and 3beta-Diol. This conversion was inhibited by flufenamic acid establishing the in vivo significance of the 3alpha/3beta-HSD activities of the AKR1C enzymes. Molecular docking simulations using available crystal structures of AKR1C1 and AKR1C2 demonstrated how 3alpha/3beta-HSD activities are achieved. The observation that AKR1Cs are a source of 3beta-tetrahydrosteroids is of physiological significance because: (i) the formation of 3beta-Diol (in contrast to 3alpha-Diol) is virtually irreversible, (ii) 3beta-Diol is a pro-apoptotic ligand for estrogen receptor beta, and (iii) 3beta-tetrahydrosteroids act as gamma-aminobutyric acid type A receptor antagonists.
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DHT can be metabolized to androstanediol by all AKR1 enzymes, and AKR1C2 in particular.
“DHT can be metabolized to androstanediol by all AKR1 enzymes, and AKR1C2 in particular [12,50]”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [50]
AKR1 enzymes preferentially act as reductases in vivo because they have nanomolar NADPH Kd values, a high cellular NADPH/NADP+ ratio, and NADPH inhibits NAD+-dependent oxidation at low micromolar concentrations.
“These enzymes preferably act as reductases in vivo since they have Kd values for NADPH in the nanomolar range, there is a high NADPH/NADP+ ratio within cells and NADPH inhibits the NAD+ dependent oxidation reactions at low μM concentrations”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [16]
In peripheral tissues, AKR1C enzymes act as 3-keto and 17-ketosteroid reductases to form 5α-DHT or to inactivate it to 3α-Diol or 3β-Diol.
“In peripheral tissues, AKR1C enzymes act as 3-keto and 17-ketosteroid reductases to catalyze either the formation of the most potent androgen 5α-dihydrotestosterone (5α-DHT) or its inactivation to yield the inactive androgens 5α-androstane-3α,17β-diol (3α-Diol) or 5α-androstane-3β,17β-diol (3β-Diol)”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [16]
AKR1C2 has the highest catalytic efficiency as a 3-ketosteroid reductase and reduces 5α-DHT to 3α-Diol.
“AKR1C2 has the highest catalytic efficiency as a 3-ketosteroid reductase and catalyzes reduction of 5α-DHT to 3α-Diol”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [16]
AKR1C3 is much less efficient as a 3-ketosteroid reductase and converts 5α-DHT mainly to 3α-Diol.
“AKR1C3 is much less efficient as a 3-ketosteroid reductase and converts 5α-DHT mainly to 3α-Diol”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [16]
COS-1, PC-3 and LNCaP cells transfected with AKR1C2 can recapitulate the reduction of 5α-DHT to 3α-Diol.
“COS-1, PC-3 and LNCaP cells transfected with AKR1C2 were able to recapitulate this reaction”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [16]
AKR1C1 forms mainly 3β-Diol, a potent ERβ agonist with anti-proliferative effects.
“AKR1C1 forms mainly 3β-Diol, a potent agonist of ERβ which exerts anti-proliferative effects”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [16]
Liver-specific AKR1C4 forms 3α-Diol with the highest kcat among AKR1C enzymes.
“Liver specific AKR1C4 forms 3α-Diol with the highest kcat among the AKR1C enzymes”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [16]
AKR1C2 inactivates 5α-DHT to the less active 3α-Diol (Kd = 10−6 M for AR).
“AKR1C2 catalyzes inactivation of 5α-DHT to yield the less active 3α-Diol (Kd = 10−6 M for the AR)”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [16]
AKR1C3 reduces Δ4-androstene-3,17-dione to testosterone (Kd = 10−9 M for AR) and 5α-androstane-3,17-dione to 5α-DHT (Kd = 10−10 M for AR).
“AKR1C3 catalyzes the reduction of Δ4-androstene-3,17-dione to form the potent androgen testosterone (Kd = 10−9 M for AR) and the reduction of 5α-androstane-3,17-dione to yield the most potent androgen 5α-DHT (Kd =10−10 M for the AR).”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [16]
5β-reduced steroids are predominantly converted to the 3α-hydroxy epimer because the 5β-reduced bent conformation sterically does not allow binding in the AKR1C active site for 3β-reduction.
“5β-reduced steroids are predominantly converted to the 3α-hydroxy epimer as the 5β-reduced bent confirmation of the A/B-ring sterically does not allow binding in the AKR1C active site for 3β-reduction [102,103].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [102]
AKR1C1 is the most important isoform for the formation of the 3β-hydroxyepimer.
“AKR1C1 is the most important isoform for the formation of the 3β-hydroxyepimer [102].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [102]
AKR1C2 is the major isoform for 3-reduction to the 3α-hydroxyepimer in peripheral tissue.
“AKR1C2 is the major isoform for 3-reduction to the 3α-hydroxyepimer in peripheral tissue”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [102]
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Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302 · see citing works
Statistical estimations in enzyme kinetics
Wilkinson, G. (1961) · Biochemical Journal · doi:10.1042/bj0800324 · Cited by 3,566 · see citing works
Paul, S. M., & Purdy, R. H. (1992) · The FASEB Journal · doi:10.1096/fasebj.6.6.1347506 · Cited by 1,328 · see citing works
PENNING, T. M., BURCZYNSKI, M. E., JEZ, J. M., HUNG, C.-F., LIN, H.-K., MA, H., MOORE, M., PALACKAL, N., & RATNAM, K. (2000) · Biochemical Journal · doi:10.1042/0264-6021:3510067 · Cited by 649 · see citing works
Self-citationPENNING, T. M., BURCZYNSKI, M. E., JEZ, J. M., HUNG, C.-F., LIN, H.-K., MA, H., MOORE, M., PALACKAL, N., & RATNAM, K. (2000) · Biochemical Journal · doi:10.1042/bj3510067 · Cited by 649 · see citing works
Self-citationNeuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives
Rupprecht, R., & Holsboer, F. (1999) · Trends in Neurosciences · doi:10.1016/s0166-2236(99)01399-5 · Cited by 636 · see citing works
A role for estrogen receptor β in the regulation of growth of the ventral prostate
Weihua, Z., Mäkelä, S., Andersson, L. C., Salmi, S., Saji, S., Webster, J. I., Jensen, E. V., Nilsson, S., Warner, M., & Gustafsson, J.-Å. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111150898 · Cited by 440 · see citing works
Molecular Endocrinology of Hydroxysteroid Dehydrogenases
Penning, T. M. (1997) · Endocrine Reviews · doi:10.1210/edrv.18.3.0302 · Cited by 436 · see citing works
Self-citationThe induction of prostatic hypertrophy in the dog with androstanediol.
Walsh, P. C., & Wilson, J. D. (1976) · Journal of Clinical Investigation · doi:10.1172/jci108353 · Cited by 422 · see citing works
Rhéaume, E., Lachance, Y., Zhao, H.-F., Breton, N., Dumont, M., Launoit, Y. D., Trudel, C., Luu-The, V., Simard, J., & Labrie, F. (1991) · Molecular Endocrinology · doi:10.1210/mend-5-8-1147 · Cited by 362 · see citing works
Weihua, Z., Lathe, R., Warner, M. N., & Gustafsson, J.-Α. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.162477299 · Cited by 328 · see citing works
Characteristics of a Highly Labile Human Type 5 17β-Hydroxysteroid Dehydrogenase1
Dufort, I., Rheault, P., Huang, X.-F., Soucy, P., & Luu-The, V. (1999) · Endocrinology · doi:10.1210/endo.140.2.6531 · Cited by 255 · see citing works
Biswas, M. G., & Russell, D. W. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.25.15959 · Cited by 224 · see citing works
Saartok, T., Dahlberg, E., & Gustafsson, J.-Α. (1984) · Endocrinology · doi:10.1210/endo-114-6-2100 · Cited by 216 · see citing works
LORENCE, M. C., MURRY, B. A., TRANT, J. M., & MASON, J. I. (1990) · Endocrinology · doi:10.1210/endo-126-5-2493 · Cited by 212 · see citing works
Lin, H.-K., Jez, J. M., Schlegel, B. P., Peehl, D. M., Pachter, J. A., & Penning, T. M. (1997) · Molecular Endocrinology · doi:10.1210/mend.11.13.0026 · Cited by 194 · see citing works
Self-citation3β-Hydroxypregnane Steroids Are Pregnenolone Sulfate-Like GABAAReceptor Antagonists
Wang, M., He, Y., Eisenman, L. N., Fields, C. T., Zeng, C.-M., Mathews, J., Benz, A. M., Fu, T., Zorumski, E. C., Steinbach, J. H., et al. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-09-03366.2002 · Cited by 169 · see citing works
Lambert, J. J., Belelli, D., Harney, S. C., Peters, J. A., & Frenguelli, B. G. (2001) · Brain Research Reviews · doi:10.1016/s0165-0173(01)00124-2 · Cited by 164 · see citing works
Energy Metabolism of the Cell: A Theoretical Treatise
Reich, J. G., & Sel'kov, E. E. (1982) · Medical Entomology and Zoology · Cited by 160 · see citing works
Burczynski, M. E., Harvey, R. G., & Penning, T. M. (1998) · Biochemistry · doi:10.1021/bi972725u · Cited by 134 · see citing works
Self-citationRižner, T. L., Lin, H. K., Peehl, D. M., Steckelbroeck, S., Bauman, D. R., & Penning, T. M. (2003) · Endocrinology · doi:10.1210/en.2002-0032 · Cited by 132 · see citing works
Self-citationSteroid 5α-reductases and 3α-hydroxysteroid dehydrogenases: key enzymes in androgen metabolism
Jin, Y., & Penning, T. M. (2001) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1053/beem.2001.0120 · Cited by 125 · see citing works
Self-citationGough, W. H., VanOoteghem, S., Sint, T., & Kedishvili, N. Y. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.31.19778 · Cited by 114 · see citing works
Characterization of a human 20alpha-hydroxysteroid dehydrogenase
Zhang, Y., Dufort, I., Rheault, P., & Luu-The, V. (2000) · Journal of Molecular Endocrinology · doi:10.1677/jme.0.0250221 · Cited by 109 · see citing works
Prostate formation in a marsupial is mediated by the testicular androgen 5α-androstane-3α,17β-diol
Shaw, G., Renfree, M. B., Leihy, M. W., Shackleton, C. H. L., Roitman, E., & Wilson, J. D. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.220412297 · Cited by 101 · see citing works
Jin, Y., Stayrook, S. E., Albert, R. H., Palackal, N. T., Penning, T. M., & Lewis, M. (2001) · Biochemistry · doi:10.1021/bi010919a · Cited by 99 · see citing works
Self-citationHigaki, Y., Usami, N., Shintani, S., Ishikura, S., El-Kabbani, O., & Hara, A. (2003) · Chemico-Biological Interactions · doi:10.1016/s0009-2797(02)00206-5 · Cited by 89 · see citing works
Molecular Characterization of a First Human 3(α→β)-Hydroxysteroid Epimerase
Huang, X.-F., & Luu-The, V. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000562200 · Cited by 89 · see citing works
Jin, W. A. N. G., Chai, X., Eriksson, U., & Napoli, J. L. (1999) · Biochemical Journal · doi:10.1042/bj3380023 · Cited by 88 · see citing works
Selective reduction of AKR1C2 in prostate cancer and its role in DHT metabolism
Ji, Q., Chang, L., Vandenberg, D. J., Stanczyk, F. Z., & Stolz, A. (2003) · The Prostate · doi:10.1002/pros.10192 · Cited by 85 · see citing works
Penning, T. M., & Talalay, P. (1983) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.80.14.4504 · Cited by 84 · see citing works
Self-citationTrauger, J. W., Jiang, A., Stearns, B. A., & LoGrasso, P. V. (2002) · Biochemistry · doi:10.1021/bi026109w · Cited by 81 · see citing works
Characterization of a Novel Type of Human Microsomal 3α-Hydroxysteroid Dehydrogenase
Chetyrkin, S. V., Belyaeva, O. V., Gough, W. H., & Kedishvili, N. Y. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102076200 · Cited by 78 · see citing works
Couture, J., Legrand, P., Cantin, L., Luu-The, V., Labrie, F., & Breton, R. (2003) · Journal of Molecular Biology · doi:10.1016/s0022-2836(03)00762-9 · Cited by 76 · see citing works
Pawlowski, J. E., & Penning, T. M. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36860-6 · Cited by 74 · see citing works
Self-citationMaitra, R., & Reynolds, J. N. (1998) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-76-9-909 · Cited by 70 · see citing works
Function of human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase in androgen metabolism
He, X., Merz, G., Yang, Y., Pullakart, R., Mehta, P. D., Schulz, H., & Yang, S. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(00)00014-7 · Cited by 69 · see citing works
Ratnam, K., Ma, H., & Penning, T. M. (1999) · Biochemistry · doi:10.1021/bi982838t · Cited by 68 · see citing works
Self-citationWang, Bäckström, & Landgren (2000) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2000.00744.x · Cited by 62 · see citing works
Gingras, S., & Simard, J. (1999) · Endocrinology · doi:10.1210/endo.140.10.7038 · Cited by 62 · see citing works
Prince, R. J., & Simmonds, M. A. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90454-f · Cited by 60 · see citing works
Further characterization of human microsomal 3α-hydroxysteroid dehydrogenase
Chetyrkin, S. V., Hu, J., Gough, W. H., Dumaual, N., & Kedishvili, N. Y. (2001) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2000.2203 · Cited by 60 · see citing works
Usami, N., Yamamoto, T., Shintani, S., Higaki, Y., Ishikura, S., Patagiri, Y., & Hara, A. (2002) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.25.441 · Cited by 59 · see citing works
Nahoum, V., Gangloff, A., Legrand, P., Zhu, D., Cantin, L., Zhorov, B. S., Luu-The, V., Labrie, F., Breton, R., & Lin, S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105610200 · Cited by 59 · see citing works
Maitra, R., & Reynolds, J. N. (1998) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y98-091 · Cited by 56 · see citing works
In vivo metabolism of 3H-dihydrotestosterone and 3H-androstanediol in adult male rats
Doorn, E. J. V., Burns, B. G., Wood, D. M., et al. (1975) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(75)90213-7 · Cited by 55 · see citing works
Characterization of the 5 -Reductase-3 -Hydroxysteroid Dehydrogenase Complex in the Human Brain
Steckelbroeck, S., Watzka, M., Reichelt, R., Hans, V., Stoffel‐Wagner, B., Heidrich, D. D., Schramm, J., BIDLINGMAIER, F., & Klingmüller, D. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.3.7325 · Cited by 54 · see citing works
Self-citationStoffel‐Wagner, B., Watzka, M., Steckelbroeck, S., Ludwig, M. Z., Clusmann, H., BIDLINGMAIER, F., Casarosa, E., Luisi, S. V., Elger, C. E., & Beyenburg, S. (2003) · Epilepsy Research · doi:10.1016/s0920-1211(03)00036-6 · Cited by 53 · see citing works
Self-citationKrieg, M., Horst, H.-J., & STERBA, M.-L. (1975) · Journal of Endocrinology · doi:10.1677/joe.0.0640529 · Cited by 53 · see citing works
Morfin, R., Stefano, S. D., Charles, J. F., et al. (1977) · Biochimie · doi:10.1016/s0300-9084(77)80173-9 · Cited by 48 · see citing works
Pirog, E. C., & Collins, D. C. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.9.5963 · Cited by 45 · see citing works
Matsuura, K., Deyashiki, Y., Sato, K., ISHIDA, N., Miwa, G., & Hara, A. (1997) · Biochemical Journal · doi:10.1042/bj3230061 · Cited by 42 · see citing works
Formation of 5α-Androstane-3α,17β-diol by Normal and Hypertrophic Human Prostate
Jacobi, G. H., & Wilson, J. D. (1977) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-44-1-107 · Cited by 36 · see citing works
Kao, L. W. L., Lloret, A. P., & Weisz, J. (1977) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(77)90282-5 · Cited by 35 · see citing works
Expression of the 17β-hydroxysteroid dehydrogenase type 5 mRNA in the human brain
Steckelbroeck, S., Watzka, M., Stoffel‐Wagner, B., Hans, V., Redel, L., Clusmann, H., Elger, C. E., BIDLINGMAIER, F., & Klingmüller, D. (2001) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(00)00432-9 · Cited by 33 · see citing works
Self-citationMAUVAIS-JARVIS, P., & Baulieu, É.-É. (1965) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-25-9-1167 · Cited by 33 · see citing works
Horst, H.-J., Dennis, M., Kaufmann, J., & Voigt, K. (1975) · European Journal of Endocrinology · doi:10.1530/acta.0.0790394 · Cited by 25 · see citing works
Stewart, M. E., Pochi, P. E., Strauss, J. S., et al. (1977) · Journal of Endocrinology · doi:10.1677/joe.0.0720385 · Cited by 24 · see citing works
Thomas, J. L., Strickler, R. C., Myers, R. P., & Covey, D. F. (1992) · Biochemistry · doi:10.1021/bi00139a014 · Cited by 23 · see citing works
Habrioux, G., Desfosses, B., Condom, R., et al. (1978) · Steroids · doi:10.1016/0039-128x(78)90100-9 · Cited by 21 · see citing works
METABOLISM AND MODE OF ACTION OF ANDROGENS IN TARGET TISSUES OF MALE RATS
Becker, H., Grabosch, E., Hoffmann, C., et al. (1973) · European Journal of Endocrinology · doi:10.1530/acta.0.0730407 · Cited by 20 · see citing works
Reduction of dihydrotestosterone to androstanediols by human female skin in-vitro
Wright, F., & Giacomini, M. (1980) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(80)90030-8 · Cited by 17 · see citing works
Gemzik, B., Jacob, S. S., Jennings, S. B., et al. (1992) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(92)90587-m · Cited by 17 · see citing works
Androgen metabolism in rat skeletal muscle in vitro
Stenstad, P., & Eik‐Nes, K. B. (1981) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(81)90203-4 · Cited by 14 · see citing works
Ofner, P., Sousa, R. L., Vena, R. L., et al. (1983) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(83)90060-2 · Cited by 13 · see citing works
Olchovsky, D., Bruno, J. F., & Berelowitz, M. (1996) · Journal of Endocrinology · doi:10.1677/joe.0.1480189 · Cited by 8 · see citing works
Androgen metabolism in vitro by human leukocytes. Variations with sex and age
Clair, P., Patricot, M. C., Mathian, B., et al. (1984) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(84)90237-1 · Cited by 7 · see citing works
Trapp, T., Tunn, S., & Krieg, M. (1992) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(92)90135-6 · Cited by 7 · see citing works
Kinoshita, Y. (1981) · Endocrinologia Japonica · doi:10.1507/endocrj1954.28.499 · Cited by 6 · see citing works
Flagged first, then by citations
Research works printed but not linked: 40
- [1]1. Simard, J. ∙ Durocher, F. ∙ Mébarki, F. ... J. Endocr. 1996; 150:S189-S207 PubMed Google Scholar
- [2]2. Penning, T.M. Endocr. Rev. 1997; 18:281-305 Crossref Scopus (404) PubMed Google Scholar
- [3]3. Jacobi, G.H. ∙ Wilson, J.D. J. Clin. Endocrinol. Metab. 1977; 44:107-115 Crossref Scopus (34) PubMed Google Scholar
- [4]4. Stewart, M.E. ∙ Pochi, P.E. ∙ Strauss, J.S. ... J. Endocrinol. 1977; 72:385-390 Crossref Scopus (22) PubMed Google Scholar
- [5]5. Wright, F. ∙ Giacomini, M. J. Steroid Biochem. 1980; 13:639-643 Crossref Scopus (17) PubMed Google Scholar
- [6]6. Kinoshita, Y. Endocrinol. Japon. 1981; 28:499-513 Crossref Scopus (6) PubMed Google Scholar
- [7]7. Clair, P. ∙ Patricot, M.C. ∙ Mathian, B. ... J. Steroid Biochem. 1984; 20:377-381 Crossref Scopus (4) PubMed Google Scholar
- [8]8. Trapp, T. ∙ Tunn, S. ∙ Krieg, M. J. Steroid Biochem. Mol. Biol. 1992; 42:321-327 Crossref Scopus (11) PubMed Google Scholar
- [9]9. Pirog, E.C. ∙ Collins, D.C. J. Clin. Endocrinol. Metab. 1999; 84:3217-3221 PubMed Google Scholar
- [10]10. Jin, Y. ∙ Penning, T.M. Best Practice Res. Clin. Endocrin. Metab. 2001; 15:79-94 Crossref Scopus (111) PubMed Google Scholar
- [11]11. van Doorn, E.J. ∙ Burns, B. ∙ Wood, D. ... J. Steroid Biochem. 1975; 6:1549-1554 Crossref Scopus (48) PubMed Google Scholar
- [12]12. Saartok, T. ∙ Dahlberg, E. ∙ Gustafsson, J.-Å. Endocrinology. 1984; 114:2100-2106 Crossref Scopus (164) PubMed Google Scholar
- [13]13. Becker, H. ∙ Grabosch, E. ∙ Hoffmann, C. ... Acta Endocrinol. 1973; 73:407-416 Crossref PubMed Google Scholar
- [14]14. Horst, H.-J. ∙ Dennis, M. ∙ Kaufmann, J. ... Acta Endocrinol. 1975; 79:394-402 Crossref PubMed Google Scholar
- [15]15. Krieg, M. ∙ Horst, H.-J. ∙ Sterba, M.-L. J. Endocrinol. 1975; 64:529-538 Crossref Scopus (49) PubMed Google Scholar
- [16]16. Kao, L.W.L. ∙ Lloret, A.P. ∙ Weisz, J. J. Steroid Biochem. 1977; 8:1109-1115 Crossref Scopus (33) PubMed Google Scholar
- [17]17. Stenstad, P. ∙ Eik-Nes, K.B. Biochim. Biophys. Acta. 1981; 663:169-176 Crossref Scopus (13) PubMed Google Scholar
- [18]18. Morfin, R.F. ∙ di Stefano, S. ∙ Charles, J.-F. ... Biochimie (Paris). 1977; 59:637-644 Crossref Scopus (50) PubMed Google Scholar
- [19]19. Offner, P. ∙ Sousa, R.L. ∙ Vena, R.L. ... J. Steroid Biochem. 1983; 18:415-423 Crossref Scopus (17) PubMed Google Scholar
- [20]20. Gemzik, B. ∙ Jacob, S. ∙ Jennings, S. ... Arch. Biochem. Biophys. 1992; 296:374-383 Crossref Scopus (19) PubMed Google Scholar
- [21]21. Mauvais-Jarvis, P. ∙ Baulieu, E.-E. J. Clin. Endocr. 1965; 25:1167-1178 Crossref Scopus (30) PubMed Google Scholar
- [22]22. Habrioux, G. ∙ Desfosses, B. ∙ Condom, R. ... Steroids. 1978; 32:61-71 Crossref Scopus (22) PubMed Google Scholar
- [23]23. Thomas, J.L. ∙ Strickler, R.C. ∙ Myers, R.P. ... Biochemistry. 1992; 31:5522-5527 Crossref Scopus (24) PubMed Google Scholar
- [24]24. Lorence, M. ∙ Murry, B.A. ∙ Trant, J.M. ... Endocrinology. 1990; 126:2493-2498 Crossref Scopus (225) PubMed Google Scholar
- [25]25. Rhéaume, E. ∙ Lachance, Y. ∙ Zhao, H.-F. ... Mol. Endocrinol. 1991; 5:1147-1157 Crossref Scopus (334) PubMed Google Scholar
- [26]26. Krebs, H.A. Symp. Soc. Exp. Biol. 1973; 27:299-318 PubMed Google Scholar
- [28]28. Wang, J. ∙ Chai, X. ∙ Eriksson, U. ... Biochem. J. 1999; 338:23-27 Crossref Scopus (76) PubMed Google Scholar
- [29]29. Gough, W.H. ∙ VanOoteghem, S. ∙ Sint, T. ... J. Biol. Chem. 1998; 273:19778-19785 Full Text Full Text (PDF) Scopus (111) PubMed Google Scholar
- [30]30. Biswas, M.G. ∙ Russell, D.W. J. Biol. Chem. 1997; 272:15959-15966 Full Text Full Text (PDF) Scopus (218) PubMed Google Scholar
- [31]31. Chetyrkin, S.V. ∙ Hu, J. ∙ Gough, W.H. ... Arch. Biochem. Biophys. 2001; 386:1-10 Crossref Scopus (57) PubMed Google Scholar
- [32]32. Chetyrkin, S.V. ∙ Belyaeva, O.V. ∙ Gough, W.H. ... J. Biol. Chem. 2001; 276:22278-22286 Full Text Full Text (PDF) Scopus (70) PubMed Google Scholar
- [33]33. He, X.-Y. ∙ Merz, G. ∙ Yang, Y.-Z. ... Biochim. Biophys. Acta. 2000; 1484:267-277 Crossref Scopus (62) PubMed Google Scholar
- [34]34. Penning, T.M. ∙ Burczynski, M.E. ∙ Jez, J.M. ... Biochem. J. 2000; 351:67-77 Crossref Scopus (568) PubMed Google Scholar
- [35]35. Jin, Y. ∙ Stayrook, S.E. ∙ Albert, R.H. ... Biochemistry. 2001; 40:10161-10168 Crossref Scopus (95) PubMed Google Scholar
- [36]36. Nahoum, V. ∙ Gangloff, A. ∙ Legrand, P. ... J. Biol. Chem. 2001; 276:42091-42098 Full Text Full Text (PDF) Scopus (55) PubMed Google Scholar
- [37]37. Couture, J.-F. ∙ Legrand, P. ∙ Cantin, L. ... J. Mol. Biol. 2003; 331:593-604 Crossref Scopus (74) PubMed Google Scholar
- [38]38. Burczynski, M.E. ∙ Harvey, R.G. ∙ Penning, T.M. Biochemistry. 1998; 37:6781-6790 Crossref Scopus (139) PubMed Google Scholar
- [39]39. Ratnam, K. ∙ Ma, H. ∙ Penning, T.M. Biochemistry. 1999; 38:7856-7864 Crossref Scopus (72) PubMed Google Scholar
- [40]40. Bradford, M.M. Anal. Biochem. 1976; 72:248-254 Crossref Scopus (229552) PubMed Google Scholar
- [41]41. Pawlowski, J.E. ∙ Penning, T.M. J. Biol. Chem. 1994; 269:13502-13510
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- Authors
- Steckelbroeck, S., Jin, Y., Gopishetty, S., Oyesanmi, B., & Penning, T. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Penning, Trevor M.
- ORCID
- Penning, Trevor M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-03
- Volume
- 279
- Issue
- 11
- Pages
- 10784-10795
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2066518128
- Cited by
- 270
- References
- 70
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 14 · 2023: 8 · 2022: 10 · 2021: 3 · 2020: 6 · 2019: 9 · 2018: 7 · 2017: 10 · 2016: 6 · 2015: 11 · 2014: 12 · 2013: 18 · 2012: 19
- FWCI
- 6.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA90744, R01CA090744)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-47015, R01DK047015)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- 3α-hydroxysteroid dehydrogenase, 3β-hydroxysteroid dehydrogenase, aldo-keto reductase superfamily, AKR1C1, AKR1C2, AKR1C3, AKR1C4, dihydrotestosterone, 3α-androstanediol, NADPH-dependent reduction, nonsteroidal anti-inflammatory drugs, estrogen receptor alpha, apoptosis, molecular docking, HepG2 cells, human hepatoma
- MeSH terms
- Androgens, Catalysis, Cell Line, Cytosol, Flufenamic Acid, Humans, Kinetics, Ligands, Models, Biological, Models, Molecular, NADP, Magnetic Resonance Spectroscopy, Recombinant Proteins, RNA, Messenger, Software, Steroids, Time Factors, 17-Hydroxysteroid Dehydrogenases, Polymerase Chain Reaction, DNA, Complementary, GABA Antagonists, Protein Isoforms
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