Ketoconazole (T3D2961)

General Function:

Steroid 17-alpha-monooxygenase activity

Specific Function:

Conversion of pregnenolone and progesterone to their 17-alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation and the 17,20-lyase reaction. Involved in sexual development during fetal life and at puberty.

Gene Name:

CYP17A1

Uniprot ID:

P05093

Molecular Weight:

57369.995 Da

References

1. Rowlands MG, Barrie SE, Chan F, Houghton J, Jarman M, McCague R, Potter GA: Esters of 3-pyridylacetic acid that combine potent inhibition of 17 alpha-hydroxylase/C17,20-lyase (cytochrome P45017 alpha) with resistance to esterase hydrolysis. J Med Chem. 1995 Oct 13;38(21):4191-7. [7473546 ]
2. Potter GA, Barrie SE, Jarman M, Rowlands MG: Novel steroidal inhibitors of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase): potential agents for the treatment of prostatic cancer. J Med Chem. 1995 Jun 23;38(13):2463-71. [7608911 ]
3. Chan FC, Potter GA, Barrie SE, Haynes BP, Rowlands MG, Houghton J, Jarman M: 3- and 4-pyridylalkyl adamantanecarboxylates: inhibitors of human cytochrome P450(17 alpha) (17 alpha-hydroxylase/C17,20-lyase). Potential nonsteroidal agents for the treatment of prostatic cancer. J Med Chem. 1996 Aug 16;39(17):3319-23. [8765515 ]
4. Ling YZ, Li JS, Liu Y, Kato K, Klus GT, Brodie A: 17-Imidazolyl, pyrazolyl, and isoxazolyl androstene derivatives. Novel steroidal inhibitors of human cytochrome C17,20-lyase (P450(17 alpha). J Med Chem. 1997 Sep 26;40(20):3297-304. [9379450 ]
5. Njar VC, Kato K, Nnane IP, Grigoryev DN, Long BJ, Brodie AM: Novel 17-azolyl steroids, potent inhibitors of human cytochrome 17 alpha-hydroxylase-C17,20-lyase (P450(17) alpha): potential agents for the treatment of prostate cancer. J Med Chem. 1998 Mar 12;41(6):902-12. [9526564 ]
6. Hartmann RW, Hector M, Haidar S, Ehmer PB, Reichert W, Jose J: Synthesis and evaluation of novel steroidal oxime inhibitors of P450 17 (17 alpha-hydroxylase/C17-20-lyase) and 5 alpha-reductase types 1 and 2. J Med Chem. 2000 Nov 2;43(22):4266-77. [11063622 ]
7. Hartmann RW, Hector M, Wachall BG, Palusczak A, Palzer M, Huch V, Veith M: Synthesis and evaluation of 17-aliphatic heterocycle-substituted steroidal inhibitors of 17alpha-hydroxylase/C17-20-lyase (P450 17). J Med Chem. 2000 Nov 16;43(23):4437-45. [11087568 ]
8. Recanatini M, Bisi A, Cavalli A, Belluti F, Gobbi S, Rampa A, Valenti P, Palzer M, Palusczak A, Hartmann RW: A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17 alpha-hydroxylase/C17,20-lyase. J Med Chem. 2001 Mar 1;44(5):672-80. [11262078 ]
9. Li JS, Li Y, Son C, Brodie AM: Synthesis and evaluation of pregnane derivatives as inhibitors of human testicular 17 alpha-hydroxylase/C17,20-lyase. J Med Chem. 1996 Oct 11;39(21):4335-9. [8863811 ]
10. Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P, Newman D Jr, Farquhar R, Guo Z, Qiu Y, Brodie AM: Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem. 2005 Apr 21;48(8):2972-84. [15828836 ]
11. Pinto-Bazurco Mendieta MA, Negri M, Jagusch C, Hille UE, Muller-Vieira U, Schmidt D, Hansen K, Hartmann RW: Synthesis, biological evaluation and molecular modelling studies of novel ACD- and ABD-ring steroidomimetics as inhibitors of CYP17. Bioorg Med Chem Lett. 2008 Jan 1;18(1):267-73. Epub 2007 Oct 30. [18024111 ]
12. Jagusch C, Negri M, Hille UE, Hu Q, Bartels M, Jahn-Hoffmann K, Pinto-Bazurco Mendieta MA, Rodenwaldt B, Muller-Vieira U, Schmidt D, Lauterbach T, Recanatini M, Cavalli A, Hartmann RW: Synthesis, biological evaluation and molecular modelling studies of methyleneimidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17). Part I: Heterocyclic modifications of the core structure. Bioorg Med Chem. 2008 Feb 15;16(4):1992-2010. Epub 2007 Nov 4. [18061460 ]
13. Heim R, Lucas S, Grombein CM, Ries C, Schewe KE, Negri M, Muller-Vieira U, Birk B, Hartmann RW: Overcoming undesirable CYP1A2 inhibition of pyridylnaphthalene-type aldosterone synthase inhibitors: influence of heteroaryl derivatization on potency and selectivity. J Med Chem. 2008 Aug 28;51(16):5064-74. doi: 10.1021/jm800377h. Epub 2008 Aug 1. [18672861 ]
14. Pinto-Bazurco Mendieta MA, Negri M, Jagusch C, Muller-Vieira U, Lauterbach T, Hartmann RW: Synthesis, biological evaluation, and molecular modeling of abiraterone analogues: novel CYP17 inhibitors for the treatment of prostate cancer. J Med Chem. 2008 Aug 28;51(16):5009-18. doi: 10.1021/jm800355c. Epub 2008 Aug 2. [18672868 ]
15. Hu Q, Negri M, Jahn-Hoffmann K, Zhuang Y, Olgen S, Bartels M, Muller-Vieira U, Lauterbach T, Hartmann RW: Synthesis, biological evaluation, and molecular modeling studies of methylene imidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17)--part II: Core rigidification and influence of substituents at the methylene bridge. Bioorg Med Chem. 2008 Aug 15;16(16):7715-27. doi: 10.1016/j.bmc.2008.07.011. Epub 2008 Jul 9. [18674917 ]
16. Lucas S, Heim R, Negri M, Antes I, Ries C, Schewe KE, Bisi A, Gobbi S, Hartmann RW: Novel aldosterone synthase inhibitors with extended carbocyclic skeleton by a combined ligand-based and structure-based drug design approach. J Med Chem. 2008 Oct 9;51(19):6138-49. doi: 10.1021/jm800683c. Epub 2008 Sep 3. [18763754 ]
17. Lucas S, Heim R, Ries C, Schewe KE, Birk B, Hartmann RW: In vivo active aldosterone synthase inhibitors with improved selectivity: lead optimization providing a series of pyridine substituted 3,4-dihydro-1H-quinolin-2-one derivatives. J Med Chem. 2008 Dec 25;51(24):8077-87. doi: 10.1021/jm800888q. [19049427 ]
18. Hille UE, Hu Q, Vock C, Negri M, Bartels M, Muller-Vieira U, Lauterbach T, Hartmann RW: Novel CYP17 inhibitors: synthesis, biological evaluation, structure-activity relationships and modelling of methoxy- and hydroxy-substituted methyleneimidazolyl biphenyls. Eur J Med Chem. 2009 Jul;44(7):2765-75. doi: 10.1016/j.ejmech.2009.01.002. Epub 2009 Jan 19. [19211174 ]
19. Hu Q, Yin L, Jagusch C, Hille UE, Hartmann RW: Isopropylidene substitution increases activity and selectivity of biphenylmethylene 4-pyridine type CYP17 inhibitors. J Med Chem. 2010 Jul 8;53(13):5049-53. doi: 10.1021/jm100400a. [20550118 ]
20. Gobbi S, Zimmer C, Belluti F, Rampa A, Hartmann RW, Recanatini M, Bisi A: Novel highly potent and selective nonsteroidal aromatase inhibitors: synthesis, biological evaluation and structure-activity relationships investigation. J Med Chem. 2010 Jul 22;53(14):5347-51. doi: 10.1021/jm100319h. [20568782 ]
21. Hu Q, Jagusch C, Hille UE, Haupenthal J, Hartmann RW: Replacement of imidazolyl by pyridyl in biphenylmethylenes results in selective CYP17 and dual CYP17/CYP11B1 inhibitors for the treatment of prostate cancer. J Med Chem. 2010 Aug 12;53(15):5749-58. doi: 10.1021/jm100317b. [20684610 ]
22. Zimmer C, Hafner M, Zender M, Ammann D, Hartmann RW, Vock CA: N-(Pyridin-3-yl)benzamides as selective inhibitors of human aldosterone synthase (CYP11B2). Bioorg Med Chem Lett. 2011 Jan 1;21(1):186-90. doi: 10.1016/j.bmcl.2010.11.040. Epub 2010 Nov 12. [21129965 ]
23. Lucas S, Negri M, Heim R, Zimmer C, Hartmann RW: Fine-tuning the selectivity of aldosterone synthase inhibitors: structure-activity and structure-selectivity insights from studies of heteroaryl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one derivatives. J Med Chem. 2011 Apr 14;54(7):2307-19. doi: 10.1021/jm101470k. Epub 2011 Mar 8. [21384875 ]
24. Stefanachi A, Favia AD, Nicolotti O, Leonetti F, Pisani L, Catto M, Zimmer C, Hartmann RW, Carotti A: Design, synthesis, and biological evaluation of imidazolyl derivatives of 4,7-disubstituted coumarins as aromatase inhibitors selective over 17-alpha-hydroxylase/C17-20 lyase. J Med Chem. 2011 Mar 24;54(6):1613-25. doi: 10.1021/jm101120u. Epub 2011 Feb 22. [21341743 ]

General Function:

Oxygen binding

Specific Function:

Catalyzes the formation of aromatic C18 estrogens from C19 androgens.

Gene Name:

CYP19A1

Uniprot ID:

P11511

Molecular Weight:

57882.48 Da

References

1. Weber MM, Will A, Adelmann B, Engelhardt D: Effect of ketoconazole on human ovarian C17,20-desmolase and aromatase. J Steroid Biochem Mol Biol. 1991 Feb;38(2):213-8. [2004042 ]
2. Voets M, Antes I, Scherer C, Muller-Vieira U, Biemel K, Marchais-Oberwinkler S, Hartmann RW: Synthesis and evaluation of heteroaryl-substituted dihydronaphthalenes and indenes: potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis. J Med Chem. 2006 Apr 6;49(7):2222-31. [16570918 ]
3. Muftuoglu Y, Mustata G: Pharmacophore modeling strategies for the development of novel nonsteroidal inhibitors of human aromatase (CYP19). Bioorg Med Chem Lett. 2010 May 15;20(10):3050-64. doi: 10.1016/j.bmcl.2010.03.113. Epub 2010 Apr 8. [20413308 ]
4. Pontius A, Krick A, Mesry R, Kehraus S, Foegen SE, Muller M, Klimo K, Gerhauser C, Konig GM: Monodictyochromes A and B, dimeric xanthone derivatives from the marine algicolous fungus Monodictys putredinis. J Nat Prod. 2008 Nov;71(11):1793-9. doi: 10.1021/np800392w. Epub 2008 Oct 21. [18939864 ]
5. Krick A, Kehraus S, Gerhauser C, Klimo K, Nieger M, Maier A, Fiebig HH, Atodiresei I, Raabe G, Fleischhauer J, Konig GM: Potential cancer chemopreventive in vitro activities of monomeric xanthone derivatives from the marine algicolous fungus Monodictys putredinis. J Nat Prod. 2007 Mar;70(3):353-60. Epub 2007 Feb 10. [17291041 ]
6. Bonfield K, Amato E, Bankemper T, Agard H, Steller J, Keeler JM, Roy D, McCallum A, Paula S, Ma L: Development of a new class of aromatase inhibitors: design, synthesis and inhibitory activity of 3-phenylchroman-4-one (isoflavanone) derivatives. Bioorg Med Chem. 2012 Apr 15;20(8):2603-13. doi: 10.1016/j.bmc.2012.02.042. Epub 2012 Feb 27. [22444875 ]
7. Tianpanich K, Prachya S, Wiyakrutta S, Mahidol C, Ruchirawat S, Kittakoop P: Radical scavenging and antioxidant activities of isocoumarins and a phthalide from the endophytic fungus Colletotrichum sp. J Nat Prod. 2011 Jan 28;74(1):79-81. doi: 10.1021/np1003752. Epub 2010 Dec 21. [21174408 ]
8. Paoletta S, Steventon GB, Wildeboer D, Ehrman TM, Hylands PJ, Barlow DJ: Screening of herbal constituents for aromatase inhibitory activity. Bioorg Med Chem. 2008 Sep 15;16(18):8466-70. doi: 10.1016/j.bmc.2008.08.034. Epub 2008 Aug 19. [18778944 ]
9. Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. [1495014 ]
10. Chan FC, Potter GA, Barrie SE, Haynes BP, Rowlands MG, Houghton J, Jarman M: 3- and 4-pyridylalkyl adamantanecarboxylates: inhibitors of human cytochrome P450(17 alpha) (17 alpha-hydroxylase/C17,20-lyase). Potential nonsteroidal agents for the treatment of prostatic cancer. J Med Chem. 1996 Aug 16;39(17):3319-23. [8765515 ]
11. Hu Q, Yin L, Jagusch C, Hille UE, Hartmann RW: Isopropylidene substitution increases activity and selectivity of biphenylmethylene 4-pyridine type CYP17 inhibitors. J Med Chem. 2010 Jul 8;53(13):5049-53. doi: 10.1021/jm100400a. [20550118 ]
12. McNulty J, Nair JJ, Vurgun N, Difrancesco BR, Brown CE, Tsoi B, Crankshaw DJ, Holloway AC: Discovery of a novel class of aldol-derived 1,2,3-triazoles: potent and selective inhibitors of human cytochrome P450 19A1 (aromatase). Bioorg Med Chem Lett. 2012 Jan 1;22(1):718-22. doi: 10.1016/j.bmcl.2011.10.039. Epub 2011 Oct 20. [22079757 ]
13. Cole PA, Robinson CH: Mechanism and inhibition of cytochrome P-450 aromatase. J Med Chem. 1990 Nov;33(11):2933-42. [2231592 ]

General Function:

Sterol 14-demethylase activity

Specific Function:

Catalyzes C14-demethylation of lanosterol; it transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.

Gene Name:

CYP51A1

Uniprot ID:

Q16850

Molecular Weight:

56805.26 Da

References

1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
2. Korosec T, Acimovic J, Seliskar M, Kocjan D, Tacer KF, Rozman D, Urleb U: Novel cholesterol biosynthesis inhibitors targeting human lanosterol 14alpha-demethylase (CYP51). Bioorg Med Chem. 2008 Jan 1;16(1):209-21. Epub 2007 Oct 4. [17964172 ]
3. Warrilow AG, Jackson CJ, Parker JE, Marczylo TH, Kelly DE, Lamb DC, Kelly SL: Identification, characterization, and azole-binding properties of Mycobacterium smegmatis CYP164A2, a homolog of ML2088, the sole cytochrome P450 gene of Mycobacterium leprae. Antimicrob Agents Chemother. 2009 Mar;53(3):1157-64. doi: 10.1128/AAC.01237-08. Epub 2008 Dec 15. [19075057 ]
4. Ekins S, Mankowski DC, Hoover DJ, Lawton MP, Treadway JL, Harwood HJ Jr: Three-dimensional quantitative structure-activity relationship analysis of human CYP51 inhibitors. Drug Metab Dispos. 2007 Mar;35(3):493-500. Epub 2006 Dec 28. [17194716 ]
5. Walker KA, Kertesz DJ, Rotstein DM, Swinney DC, Berry PW, So OY, Webb AS, Watson DM, Mak AY, Burton PM, et al.: Selective inhibition of mammalian lanosterol 14 alpha-demethylase: a possible strategy for cholesterol lowering. J Med Chem. 1993 Jul 23;36(15):2235-7. [8340925 ]

General Function:

Xenobiotic-transporting atpase activity

Specific Function:

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.

Gene Name:

ABCB1

Uniprot ID:

P08183

Molecular Weight:

141477.255 Da

References

1. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. [12699389 ]
2. Choo EF, Leake B, Wandel C, Imamura H, Wood AJ, Wilkinson GR, Kim RB: Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos. 2000 Jun;28(6):655-60. [10820137 ]
3. Wang EJ, Casciano CN, Clement RP, Johnson WW: Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors. Biochem Biophys Res Commun. 2001 Nov 30;289(2):580-5. [11716514 ]
4. Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW: Interaction of common azole antifungals with P glycoprotein. Antimicrob Agents Chemother. 2002 Jan;46(1):160-5. [11751127 ]
5. Pajeva IK, Wiese M: Pharmacophore model of drugs involved in P-glycoprotein multidrug resistance: explanation of structural variety (hypothesis). J Med Chem. 2002 Dec 19;45(26):5671-86. [12477351 ]

General Function:

Oxidoreductase activity

Specific Function:

Has a role in maintaining calcium homeostasis. Catalyzes the NADPH-dependent 24-hydroxylation of calcidiol (25-hydroxyvitamin D(3)) and calcitriol (1-alpha,25-dihydroxyvitamin D(3)). The enzyme can perform up to 6 rounds of hydroxylation of calcitriol leading to calcitroic acid. It also shows 23-hydroxylating activity leading to 1-alpha,25-dihydroxyvitamin D(3)-26,23-lactone as end product.

Gene Name:

CYP24A1

Uniprot ID:

Q07973

Molecular Weight:

58874.695 Da

References

1. Aboraia AS, Yee SW, Gomaa MS, Shah N, Robotham AC, Makowski B, Prosser D, Brancale A, Jones G, Simons C: Synthesis and CYP24A1 inhibitory activity of N-(2-(1H-imidazol-1-yl)-2-phenylethyl)arylamides. Bioorg Med Chem. 2010 Jul 15;18(14):4939-46. doi: 10.1016/j.bmc.2010.06.011. Epub 2010 Jun 9. [20594862 ]
2. Kahraman M, Sinishtaj S, Dolan PM, Kensler TW, Peleg S, Saha U, Chuang SS, Bernstein G, Korczak B, Posner GH: Potent, selective and low-calcemic inhibitors of CYP24 hydroxylase: 24-sulfoximine analogues of the hormone 1alpha,25-dihydroxyvitamin D(3). J Med Chem. 2004 Dec 30;47(27):6854-63. [15615534 ]
3. Aboraia AS, Makowski B, Bahja A, Prosser D, Brancale A, Jones G, Simons C: Synthesis and CYP24A1 inhibitory activity of (E)-2-(2-substituted benzylidene)- and 2-(2-substituted benzyl)-6-methoxy-tetralones. Eur J Med Chem. 2010 Oct;45(10):4427-34. doi: 10.1016/j.ejmech.2010.07.001. Epub 2010 Jul 8. [20655626 ]
4. Zhu J, Barycki R, Chiellini G, Deluca HF: Screening of selective inhibitors of 1alpha,25-dihydroxyvitamin D3 24-hydroxylase using recombinant human enzyme expressed in Escherichia coli. Biochemistry. 2010 Dec 14;49(49):10403-11. doi: 10.1021/bi101488p. Epub 2010 Nov 18. [21058632 ]

General Function:

Steroid 11-beta-monooxygenase activity

Specific Function:

Preferentially catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone.

Gene Name:

CYP11B2

Uniprot ID:

P19099

Molecular Weight:

57559.62 Da

References

1. Pinto-Bazurco Mendieta MA, Negri M, Jagusch C, Muller-Vieira U, Lauterbach T, Hartmann RW: Synthesis, biological evaluation, and molecular modeling of abiraterone analogues: novel CYP17 inhibitors for the treatment of prostate cancer. J Med Chem. 2008 Aug 28;51(16):5009-18. doi: 10.1021/jm800355c. Epub 2008 Aug 2. [18672868 ]
2. Hu Q, Yin L, Jagusch C, Hille UE, Hartmann RW: Isopropylidene substitution increases activity and selectivity of biphenylmethylene 4-pyridine type CYP17 inhibitors. J Med Chem. 2010 Jul 8;53(13):5049-53. doi: 10.1021/jm100400a. [20550118 ]
3. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]
4. Ulmschneider S, Muller-Vieira U, Klein CD, Antes I, Lengauer T, Hartmann RW: Synthesis and evaluation of (pyridylmethylene)tetrahydronaphthalenes/-indanes and structurally modified derivatives: potent and selective inhibitors of aldosterone synthase. J Med Chem. 2005 Mar 10;48(5):1563-75. [15743198 ]

References

1. Trachtenberg J, Zadra J: Steroid synthesis inhibition by ketoconazole: sites of action. Clin Invest Med. 1988 Feb;11(1):1-5. [2966691 ]
2. Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D: Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest. 1983 May;71(5):1495-9. [6304148 ]

General Function:

Steroid 11-beta-monooxygenase activity

Specific Function:

Has steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochrome P450 XIB.

Gene Name:

CYP11B1

Uniprot ID:

P15538

Molecular Weight:

57572.44 Da

References

1. Hu Q, Yin L, Jagusch C, Hille UE, Hartmann RW: Isopropylidene substitution increases activity and selectivity of biphenylmethylene 4-pyridine type CYP17 inhibitors. J Med Chem. 2010 Jul 8;53(13):5049-53. doi: 10.1021/jm100400a. [20550118 ]
2. Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic Acids Res. 2007 Jan;35(Database issue):D198-201. Epub 2006 Dec 1. [17145705 ]

General Function:

Vitamin d3 25-hydroxylase activity

Specific Function:

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).

Gene Name:

CYP3A4

Uniprot ID:

P08684

Molecular Weight:

57342.67 Da

References

1. Pinto-Bazurco Mendieta MA, Negri M, Jagusch C, Muller-Vieira U, Lauterbach T, Hartmann RW: Synthesis, biological evaluation, and molecular modeling of abiraterone analogues: novel CYP17 inhibitors for the treatment of prostate cancer. J Med Chem. 2008 Aug 28;51(16):5009-18. doi: 10.1021/jm800355c. Epub 2008 Aug 2. [18672868 ]
2. Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. [1495014 ]

General Function:

Steroid hydroxylase activity

Specific Function:

Specifically catalyzes the 21-hydroxylation of steroids. Required for the adrenal synthesis of mineralocorticoids and glucocorticoids.

Gene Name:

CYP21A2

Uniprot ID:

P08686

Molecular Weight:

55886.805 Da

References

1. Trachtenberg J, Zadra J: Steroid synthesis inhibition by ketoconazole: sites of action. Clin Invest Med. 1988 Feb;11(1):1-5. [2966691 ]
2. Rotstein DM, Kertesz DJ, Walker KA, Swinney DC: Stereoisomers of ketoconazole: preparation and biological activity. J Med Chem. 1992 Jul 24;35(15):2818-25. [1495014 ]

References

1. Trachtenberg J, Zadra J: Steroid synthesis inhibition by ketoconazole: sites of action. Clin Invest Med. 1988 Feb;11(1):1-5. [2966691 ]

General Function:

Iron ion binding

Specific Function:

Catalyzes the conversion of 25-hydroxyvitamin D3 (25(OH)D) to 1-alpha,25-dihydroxyvitamin D3 (1,25(OH)2D) plays an important role in normal bone growth, calcium metabolism, and tissue differentiation.

Gene Name:

CYP27B1

Uniprot ID:

O15528

Molecular Weight:

56503.475 Da

References

1. Zhu J, Barycki R, Chiellini G, Deluca HF: Screening of selective inhibitors of 1alpha,25-dihydroxyvitamin D3 24-hydroxylase using recombinant human enzyme expressed in Escherichia coli. Biochemistry. 2010 Dec 14;49(49):10403-11. doi: 10.1021/bi101488p. Epub 2010 Nov 18. [21058632 ]

General Function:

Zinc ion binding

Specific Function:

Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.

Gene Name:

AR

Uniprot ID:

P10275

Molecular Weight:

98987.9 Da

References

1. Eil C: Ketoconazole binds to the human androgen receptor. Horm Metab Res. 1992 Aug;24(8):367-70. [1526623 ]

General Function:

Transporter activity

Specific Function:

Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.

Gene Name:

ABCB11

Uniprot ID:

O95342

Molecular Weight:

146405.83 Da

References

1. Wang EJ, Casciano CN, Clement RP, Johnson WW: Fluorescent substrates of sister-P-glycoprotein (BSEP) evaluated as markers of active transport and inhibition: evidence for contingent unequal binding sites. Pharm Res. 2003 Apr;20(4):537-44. [12739759 ]

General Function:

Nad binding

Specific Function:

Not Available

Gene Name:

MDH1

Uniprot ID:

P40925

Molecular Weight:

36425.795 Da

References

1. Seidler J, McGovern SL, Doman TN, Shoichet BK: Identification and prediction of promiscuous aggregating inhibitors among known drugs. J Med Chem. 2003 Oct 9;46(21):4477-86. [14521410 ]

General Function:

Zinc ion binding

Specific Function:

Binds and transactivates the retinoic acid response elements that control expression of the retinoic acid receptor beta 2 and alcohol dehydrogenase 3 genes. Transactivates both the phenobarbital responsive element module of the human CYP2B6 gene and the CYP3A4 xenobiotic response element.

Gene Name:

NR1I3

Uniprot ID:

Q14994

Molecular Weight:

39942.145 Da

References

1. Dring AM, Anderson LE, Qamar S, Stoner MA: Rational quantitative structure-activity relationship (RQSAR) screen for PXR and CAR isoform-specific nuclear receptor ligands. Chem Biol Interact. 2010 Dec 5;188(3):512-25. doi: 10.1016/j.cbi.2010.09.018. Epub 2010 Oct 20. [20869355 ]

General Function:

Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization

Specific Function:

Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation.

Gene Name:

KCNH2

Uniprot ID:

Q12809

Molecular Weight:

126653.52 Da

References

1. Chiu PJ, Marcoe KF, Bounds SE, Lin CH, Feng JJ, Lin A, Cheng FC, Crumb WJ, Mitchell R: Validation of a [3H]astemizole binding assay in HEK293 cells expressing HERG K+ channels. J Pharmacol Sci. 2004 Jul;95(3):311-9. [15272206 ]

General Function:

Virus receptor activity

Specific Function:

The hepatic sodium/bile acid uptake system exhibits broad substrate specificity and transports various non-bile acid organic compounds as well. It is strictly dependent on the extracellular presence of sodium.(Microbial infection) Acts as a receptor for hepatitis B virus.

Gene Name:

SLC10A1

Uniprot ID:

Q14973

Molecular Weight:

38118.64 Da

References

1. Kim RB, Leake B, Cvetkovic M, Roden MM, Nadeau J, Walubo A, Wilkinson GR: Modulation by drugs of human hepatic sodium-dependent bile acid transporter (sodium taurocholate cotransporting polypeptide) activity. J Pharmacol Exp Ther. 1999 Dec;291(3):1204-9. [10565843 ]

General Function:

Serotonin:sodium symporter activity

Specific Function:

Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.

Gene Name:

SLC6A4

Uniprot ID:

P31645

Molecular Weight:

70324.165 Da

References

1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

General Function:

Transcription regulatory region dna binding

Specific Function:

Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues. Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1. Inhibits PER1 by repressing the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of PER1.

Gene Name:

AHR

Uniprot ID:

P35869

Molecular Weight:

96146.705 Da

References

1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

General Function:

Zinc ion binding

Specific Function:

Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.

Gene Name:

NR1I2

Uniprot ID:

O75469

Molecular Weight:

49761.245 Da

References

1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

General Function:

Zinc ion binding

Specific Function:

Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.

Gene Name:

NR1H4

Uniprot ID:

Q96RI1

Molecular Weight:

55913.915 Da

References

1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

General Function:

Zinc ion binding

Specific Function:

Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of cellular differentiation, immunity, peripheral circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target gene regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates the circadian expression of clock genes such as CRY1, ARNTL/BMAL1 and NR1D1 in peripheral tissues and in a tissue-selective manner. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORC-mediated activation of the expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Involved in the regulation of the rhythmic expression of genes involved in glucose and lipid metabolism, including PLIN2 and AVPR1A. Negative regulator of adipocyte differentiation through the regulation of early phase genes expression, such as MMP3. Controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. In liver, has specific and redundant functions with RORA as positive or negative modulator of expression of genes encoding phase I and Phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as SULT1E1. Also plays also a role in the regulation of hepatocyte glucose metabolism through the regulation of G6PC and PCK1. Regulates the rhythmic expression of PROX1 and promotes its nuclear localization (By similarity). Plays an indispensable role in the induction of IFN-gamma dependent anti-mycobacterial systemic immunity (PubMed:26160376).Isoform 2: Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes and Peyer's patches. Required for the generation of LTi (lymphoid tissue inducer) cells. Regulates thymocyte survival through DNA-binding on ROREs of target gene promoter regions and recruitment of coactivaros via the AF-2. Also plays a key role, downstream of IL6 and TGFB and synergistically with RORA, for lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. May also play a role in the pre-TCR activation cascade leading to the maturation of alpha/beta T-cells and may participate in the regulation of DNA accessibility in the TCR-J(alpha) locus.

Gene Name:

RORC

Uniprot ID:

P51449

Molecular Weight:

58194.845 Da

References

1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

General Function:

Zinc ion binding

Specific Function:

NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and alpha-tubulin as well as many other proteins such as key transcription factors. Participates in the modulation of multiple and diverse biological processes such as cell cycle control, genomic integrity, microtubule dynamics, cell differentiation, metabolic networks, and autophagy. Plays a major role in the control of cell cycle progression and genomic stability. Functions in the antephase checkpoint preventing precocious mitotic entry in response to microtubule stress agents, and hence allowing proper inheritance of chromosomes. Positively regulates the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex activity by deacetylating CDC20 and FZR1, then allowing progression through mitosis. Associates both with chromatin at transcriptional start sites (TSSs) and enhancers of active genes. Plays a role in cell cycle and chromatin compaction through epigenetic modulation of the regulation of histone H4 'Lys-20' methylation (H4K20me1) during early mitosis. Specifically deacetylates histone H4 at 'Lys-16' (H4K16ac) between the G2/M transition and metaphase enabling H4K20me1 deposition by SETD8 leading to ulterior levels of H4K20me2 and H4K20me3 deposition throughout cell cycle, and mitotic S-phase progression. Deacetylates SETD8 modulating SETD8 chromatin localization during the mitotic stress response. Deacetylates also histone H3 at 'Lys-57' (H3K56ac) during the mitotic G2/M transition. Upon bacterium Listeria monocytogenes infection, deacetylates 'Lys-18' of histone H3 in a receptor tyrosine kinase MET- and PI3K/Akt-dependent manner, thereby inhibiting transcriptional activity and promoting late stages of listeria infection. During oocyte meiosis progression, may deacetylate histone H4 at 'Lys-16' (H4K16ac) and alpha-tubulin, regulating spindle assembly and chromosome alignment by influencing microtubule dynamics and kinetochore function. Deacetylates alpha-tubulin at 'Lys-40' and hence controls neuronal motility, oligodendroglial cell arbor projection processes and proliferation of non-neuronal cells. Phosphorylation at Ser-368 by a G1/S-specific cyclin E-CDK2 complex inactivates SIRT2-mediated alpha-tubulin deacetylation, negatively regulating cell adhesion, cell migration and neurite outgrowth during neuronal differentiation. Deacetylates PARD3 and participates in the regulation of Schwann cell peripheral myelination formation during early postnatal development and during postinjury remyelination. Involved in several cellular metabolic pathways. Plays a role in the regulation of blood glucose homeostasis by deacetylating and stabilizing phosphoenolpyruvate carboxykinase PCK1 activity in response to low nutrient availability. Acts as a key regulator in the pentose phosphate pathway (PPP) by deacetylating and activating the glucose-6-phosphate G6PD enzyme, and therefore, stimulates the production of cytosolic NADPH to counteract oxidative damage. Maintains energy homeostasis in response to nutrient deprivation as well as energy expenditure by inhibiting adipogenesis and promoting lipolysis. Attenuates adipocyte differentiation by deacetylating and promoting FOXO1 interaction to PPARG and subsequent repression of PPARG-dependent transcriptional activity. Plays a role in the regulation of lysosome-mediated degradation of protein aggregates by autophagy in neuronal cells. Deacetylates FOXO1 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagy. Deacetylates a broad range of transcription factors and co-regulators regulating target gene expression. Deacetylates transcriptional factor FOXO3 stimulating the ubiquitin ligase SCF(SKP2)-mediated FOXO3 ubiquitination and degradation. Deacetylates HIF1A and therefore promotes HIF1A degradation and inhibition of HIF1A transcriptional activity in tumor cells in response to hypoxia. Deacetylates RELA in the cytoplasm inhibiting NF-kappaB-dependent transcription activation upon TNF-alpha stimulation. Inhibits transcriptional activation by deacetylating p53/TP53 and EP300. Deacetylates also EIF5A. Functions as a negative regulator on oxidative stress-tolerance in response to anoxia-reoxygenation conditions. Plays a role as tumor suppressor.Isoform 1: Deacetylates EP300, alpha-tubulin and histone H3 and H4.Isoform 2: Deacetylates EP300, alpha-tubulin and histone H3 and H4.Isoform 5: Lacks deacetylation activity.

Gene Name:

SIRT2

Uniprot ID:

Q8IXJ6

Molecular Weight:

43181.7 Da

References

1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

General Function:

Zinc ion binding

Specific Function:

Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Recruited to promoters via its interaction with BAZ1B/WSTF which mediates the interaction with acetylated histones, an essential step for VDR-promoter association. Plays a central role in calcium homeostasis.

Gene Name:

VDR

Uniprot ID:

P11473

Molecular Weight:

48288.64 Da

References

1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

General Function:

Transcriptional activator activity, rna polymerase ii core promoter proximal region sequence-specific binding

Specific Function:

Transcriptional activator required for lipid homeostasis. Regulates transcription of the LDL receptor gene as well as the fatty acid and to a lesser degree the cholesterol synthesis pathway (By similarity). Binds to the sterol regulatory element 1 (SRE-1) (5'-ATCACCCCAC-3'). Has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3').

Gene Name:

SREBF1

Uniprot ID:

P36956

Molecular Weight:

121673.6 Da

References

1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]