In vivo and in vitro characterization of a first-in-class novel azole analog that targets pregnane X receptor activation

Molecular Pharmacology

Volumn 80, Issue 1, 2011, Pages 124-135

  Venkatesh, Madhukumar ^a   Wang, Hongwei ^a   Cayer, Julie ^b   Leroux, Melissa ^b   Salvail, Dany ^b   Das, Bhaskar ^a   Wrobel, Jay E ^c   Mani, Sridhar ^a  

^a ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^b IPS Therapeutique Inc   (Canada)

^c Fox Chase Chemical Diversity Center Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

7 ETHYL 10 HYDROXYCAMPTOTHECIN; [1 [4 [4 [[2 (2,4 DIFLUOROPHENYL) 2 METHYL 1,3 DIOXOLAN 4 YL]METHOXY]PHENYL]PIPERAZIN 1 YL]ETHANONE; BROMETHOL; CELL NUCLEUS RECEPTOR; FLB 12; HEPCIDIN; HORMONE RECEPTOR BLOCKING AGENT; KETOCONAZOLE; PARACETAMOL; PREGNANE X RECEPTOR; PYRROLE DERIVATIVE; RIFAMPICIN; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BLOOD; CANCER CELL; COLON CANCER; CONCENTRATION RESPONSE; DRUG ANTAGONISM; DRUG INHIBITION; DRUG TARGETING; GENE EXPRESSION; IN VITRO STUDY; IN VIVO STUDY; INTESTINE; LIVER; LIVER CELL; LIVER TOXICITY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION;

ANIMALS; AZOLES; CELL LINE; CELLS, CULTURED; CHROMATOGRAPHY, LIQUID; HUMANS; MICE; MICE, INBRED C57BL; PATCH-CLAMP TECHNIQUES; RECEPTORS, STEROID; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; TANDEM MASS SPECTROMETRY;

EID: 79959288391     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.111.071787     Document Type: Article

References (38)

1. Biswas A, Mani S, Redinbo MR, Krasowski MD, Li H, and Ekins S (2009) Elucidating the 'Jekyll and Hyde' nature of PXR: the case for discovering antagonists or allosteric antagonists. Pharm Res 26:1807-1815.
2. Buchi KN, Gray PD, and Tolman KG (1986) Ketoconazole hepatotoxicity: an in vitro model. Biochem Pharmacol 35:2845-2847. (Pubitemid 16051539)
3. Casley WL, Ogrodowczyk C, Larocque L, Jaentschke B, LeBlanc-Westwood C, Menzies JA, Whitehouse L, Hefford MA, Aubin RA, Thorn CF, Whitehead AS, and Li X (2007) Cytotoxic doses of ketoconazole affect expression of a subset of hepatic genes. J Toxicol Environ Health A 70:1946-1955. (Pubitemid 350034910)
4. Cheng J, Ma X, Krausz KW, Idle JR, and Gonzalez FJ (2009) Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminopheninduced toxicity. Drug Metab Dispos 37:1611-1621.
5. Chong MP, Barritt GJ, and Crouch MF (2004) Insulin potentiates EGFR activation and signaling in fibroblasts. Biochem Biophys Res Commun 322:535-541. (Pubitemid 39490337)
6. Chrencik JE, Orans J, Moore LB, Xue Y, Peng L, Collins JL, Wisely GB, Lambert MH, Kliewer SA, and Redinbo MR (2005) Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin. Mol Endocrinol 19:1125-1134. (Pubitemid 40594113)
7. Cobellis L, Colacurci N, Trabucco E, Carpentiero C, and Grumetto L (2009) Measurement of bisphenol A and bisphenol B levels in human blood sera from healthy and endometriotic women. Biomed Chromatogr 23:1186-1190.
8. Creusot N, Kinani S, Balaguer P, Tapie N, LeMenach K, Maillot-Maréchal E, Porcher JM, Budzinski H, and Aït-Aïssa S (2010) Evaluation of an hPXR reporter gene assay for the detection of aquatic emerging pollutants: screening of chemicals and application to water samples. Anal Bioanal Chem 396:569-583.
9. Das BC, Madhukumar AV, Anguiano J, Kim S, Sinz M, Zvyaga TA, Power EC, Ganellin CR, and Mani S (2008) Synthesis of novel ketoconazole derivatives as inhibitors of the human pregnane X receptor (PXR; NR1I2; also termed SXR, PAR). Bioorg Med Chem Lett 18:3974-3977.
10. Ekins S, Chang C, Mani S, Krasowski MD, Reschly EJ, Iyer M, Kholodovych V, Ai N, Welsh WJ, Sinz M, et al. (2007) Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites. Mol Pharmacol 72:592-603. (Pubitemid 47347294)
11. Ekins S, Kholodovych V, Ai N, Sinz M, Gal J, Gera L, Welsh WJ, Bachmann K, and Mani S (2008) Computational discovery of novel low micromolar human pregnane X receptor antagonists. Mol Pharmacol 74:662-672.
12. Gergely P, Nékám K, Láng I, Kalmár L, González-Cabello R, and Perl A (1984) Ketoconazole in vitro inhibits mitogen-induced blastogenesis, antibody-dependent cellular cytotoxicity, natural killer activity and random migration of human leukocytes. Immunopharmacology 7:167-170.
13. Guo GL, Moffit JS, Nicol CJ, Ward JM, Aleksunes LA, Slitt AL, Kliewer SA, Manautou JE, and Gonzalez FJ (2004) Enhanced acetaminophen toxicity by activation of the pregnane X receptor. Toxicol Sci 82:374-380. (Pubitemid 39600064)
14. Gupta D, Venkatesh M, Wang H, Kim S, Sinz M, Goldberg GL, Whitney K, Longley C, and Mani S (2008) Expanding the roles for pregnane X receptor in cancer: proliferation and drug resistance in ovarian cancer. Clin Cancer Res 14:5332-5340.
15. Harmsen S, Meijerman I, Febus CL, Maas-Bakker RF, Beijnen JH, and Schellens JH (2009) PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line. Cancer Chemother Pharmacol 66:765-771.
16. Huang H, Wang H, Sinz M, Zoeckler M, Staudinger J, Redinbo MR, Teotico DG, Locker J, Kalpana GV, and Mani S (2007) Inhibition of drug metabolism by blocking the activation of nuclear receptors by ketoconazole. Oncogene 26:258-268. (Pubitemid 46095736)
17. Kinobe RT, Dercho RA, Vlahakis JZ, Brien JF, Szarek WA, and Nakatsu K (2006) Inhibition of the enzymatic activity of heme oxygenases by azole-based antifungal drugs. J Pharmacol Exp Ther 319:277-284.
18. Kortagere S, Krasowski MD, Reschly EJ, Venkatesh M, Mani S, and Ekins S (2010) Evaluation of computational docking to identify pregnane X receptor agonists in the ToxCast database. Environ Health Perspect 118:1412-1417.
19. Lee WM (1995) Drug-induced hepatotoxicity. N Engl J Med 333:1118-1127.
20. Leroy D, Missotten M, Waltzinger C, Martin T, and Scheer A (2007) G protein-coupled receptor-mediated ERK1/2 phosphorylation: towards a generic sensor of GPCR activation. J Recept Signal Transduct Res 27:83-97.
21. Lewis JH, Zimmerman HJ, Benson GD, and Ishak KG (1984) Hepatic injury associated with ketoconazole therapy. Analysis of 33 cases. Gastroenterology 86:503-513. (Pubitemid 14154661)
22. Loose DS, Stover EP, and Feldman D (1983) Ketoconazole binds to glucocorticoid receptors and exhibits glucocorticoid antagonist activity in cultured cells. J Clin Invest 72:404-408. (Pubitemid 13025883)
23. Mani S, Huang H, Sundarababu S, Liu W, Kalpana G, Smith AB, and Horwitz SB (2005) Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Clin Cancer Res 11:6359-6369. (Pubitemid 41262968)
24. Nardi A and Olesen SP (2008) BK channel modulators: a comprehensive overview. Curr Med Chem 15:1126-1146. (Pubitemid 352002981)
25. Osmond RI, Sheehan A, Borowicz R, Barnett E, Harvey G, Turner C, Brown A, Crouch MF, and Dyer AR (2005) GPCR screening via ERK 1/2: a novel platform for screening G protein-coupled receptors. J Biomol Screen 10:730-737. (Pubitemid 41476808)
26. Power EC, Ganellin CR, and Benton DC (2006) Partial structures of ketoconazole as modulators of the large conductance calcium-activated potassium channel (BK(Ca)). Bioorg Med Chem Lett 16:887-890. (Pubitemid 43059845)
27. Raynal C, Pascussi JM, Leguelinel G, Breuker C, Kantar J, Lallemant B, Poujol S, Bonnans C, Joubert D, Hollande F, et al. (2010) A Pregnane X Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation. Mol Cancer 9:46.
28. Rodriguez RJ and Acosta D Jr (1997) N-deacetyl ketoconazole-induced hepatotoxicity in a primary culture system of rat hepatocytes. Toxicology 117:123-131. (Pubitemid 27087486)
29. Rodriguez RJ and Buckholz CJ (2003) Hepatotoxicity of ketoconazole in Sprague-Dawley rats: glutathione depletion, flavin-containing monooxygenases-mediated bioactivation and hepatic covalent binding. Xenobiotica 33:429-441. (Pubitemid 36688118)
30. Rodriguez RJ, Proteau PJ, Marquez BL, Hetherington CL, Buckholz CJ, and O'Connell KL (1999) Flavin-containing monooxygenase-mediated metabolism of N-deacetyl ketoconazole by rat hepatic microsomes. Drug Metab Dispos 27:880-886. (Pubitemid 29347587)
31. Seglen PO (1976) Preparation of isolated rat liver cells. Methods Cell Biol 13:29-83.
32. Takeshita A, Koibuchi N, Oka J, Taguchi M, Shishiba Y, and Ozawa Y (2001) Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription. Eur J Endocrinol 145:513-517. (Pubitemid 32927081)
33. Takeshita A, Taguchi M, Koibuchi N, and Ozawa Y (2002) Putative role of the orphan nuclear receptor SXR (steroid and xenobiotic receptor) in the mechanism of CYP3A4 inhibition by xenobiotics. J Biol Chem 277:32453-32458. (Pubitemid 34984746)
34. Wang H, Huang H, Li H, Teotico DG, Sinz M, Baker SD, Staudinger J, Kalpana G, Redinbo MR, and Mani S (2007) Activated pregnenolone X-receptor is a target for ketoconazole and its analogs. Clin Cancer Res 13:2488-2495. (Pubitemid 46698601)
35. Wang H, Li H, Moore LB, Johnson MD, Maglich JM, Goodwin B, Ittoop OR, Wisely B, Creech K, Parks DJ, et al. (2008) The phytoestrogen coumestrol is a naturally occurring antagonist of the human pregnane X receptor. Mol Endocrinol 22:838-857. (Pubitemid 351482821)
36. Wolf KK, Wood SG, Hunt JA, Walton-Strong BW, Yasuda K, Lan L, Duan SX, Hao Q, Wrighton SA, Jeffery EH, Evans RM, Szakacs JG, von Moltke LL, Greenblatt DJ, Court MH, Schuetz EG, Sinclair PR, and Sinclair JF (2005) Role of the nuclear receptor pregnane X receptor in acetaminophen hepatotoxicity. Drug Metab Dispos 33:1827-1836. (Pubitemid 41697268)
37. Yong WP, Ramirez J, Innocenti F, and Ratain MJ (2005) Effects of ketoconazole on glucuronidation by UDP-glucuronosyltransferase enzymes. Clin Cancer Res 11:6699-6704. (Pubitemid 41339012)
38. Yoshida K and Niwa T (2006) Quantitative structure-activity relationship studies on inhibition of HERG potassium channels. J Chem Inf Model 46:1371-1378. (Pubitemid 43999180)