Steroid-activated nuclear receptors and uses therefor

Details Steroid-activated nuclear receptors and uses therefor Steroid-activated nuclear receptors and uses therefor

2007-05-08

2007-05-08

Ketter, James (Department: 1636)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

Reexamination Certificate

active

10081555

ABSTRACT:
A novel nuclear receptor, termed the steroid and xenobiotic receptor (SXR), a broad-specificity sensing receptor that is a novel branch of the nuclear receptor superfamily, has been discovered. SXR forms a heterodimer with RXR that can bind to and induce transcription from response elements present in steroid-inducible cytochrome P450 genes in response to hundreds of natural and synthetic compounds with biological activity, including therapeutic steroids as well as dietary steroids and lipids. Instead of hundreds of receptors, one for each inducing compound, the invention SXR receptors monitor aggregate levels of inducers to trigger production of metabolizing enzymes in a coordinated metabolic pathway. Agonists and antagonists of SXR are administered to subjects to achieve a variety of therapeutic goals dependent upon modulating metabolism of one or more endogenous steroids or xenobiotics to establish homeostasis. An assay is provided for identifying steroid drugs that are likely to cause drug interaction if administered to a subject in therapeutic amounts. Transgenic animals are also provided which express human SXR, thereby serving as useful models for human response to various agents which potentially impact P450-dependent metabolic processes.

REFERENCES:
patent: 4160152 (1979-07-01), Wightman et al.
patent: 4256108 (1981-03-01), Theeuwes
patent: 4265874 (1981-05-01), Bonsen et al.
patent: WO 99/19354 (1999-04-01), None
patent: WO 99/48915 (1999-09-01), None
patent: WO 99/61622 (1999-12-01), None
Adlercreutz and Mazur, “Phyto-oestrogens and Western Diseases”Ann. Med.29:95-120 (1997).
Altschul, et al., “Basic Local Alignment Search Tool”J. Mol. Biol.215:403-140 (1990).
Baes, et al., “A New Orphan Member of the Nuclear Hormone Receptor Superfamily That Interacts with a Subset of Retinoic Acid Response Elements”Molecular and Cellular Biology14 (3):1544-1552 (1994).
Bahouth, et al., “Immunological approaches for probing receptor structure and function”TIPS(12):338-343 (1991).
Beato, et al., “Steroid Hormone Receptors: Many Actors in Search of Plot”Cell83:851-857 (1995).
Blumberg, et al., “Novel retinoic acid receptor ligands inXenopusembryos”Proc. Natl. Acad. Sci. USA93:4873-4878 (1996).
Burger, et al., “Paradoxical transcriptional activation rat liver cytochrome P-450 3A1 by dexamethasone and the antiglucocorticoid pregnenolone 16β-carbonitrile: Analysis by transient transfection into primary monolayer cultures of adult rat hepatocytes”Proc. Natl. Acad. Sci. USA89:2145-2149 (1992).
Current Protocols in Molecular Biology(Ausubel et al., eds.) John Wiley and Sons, New York (1989).
Denison and Whitlock, Jr., “Xenobiotic-inducible Transcription of Cytochrome P450 Genes”The Journal of Biological Chemistry270 (31):18175-18178 (1995).
Devereaux, et al., “A comprehensive set of sequence analysis programs for the VAX”Nucleic Acids Research12 (1):387-395 (1984).
Elshourbagy and Guzelian, “Separation, Purification, and Characterization of a Novel Form of Hepatic Cytochrome P-450 from Rats Treated with Pregnenolone-16α-carbonitrile”The Journal of Biological Chemistry255 (4):1279-1285 (1980).
Enmark and Gustafsson, “Orphan Nuclear Receptors-The First Eight Years”Molecular Endocrinology10 (11):1293-1307 (1996).
Evans, R.M., “The Steroid and Thyroid Hormone Receptor Superfamily”Science240:889-895 (1988).
Fernandez-Salguero and Gonzalez, “The CYP2A gene subfamily: species differences, regulation, catalytic activities and role in chemical carcinogenesis”Pharmacogenetics5:S123-S128 (1995).
Forman, et al., “Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ”Proc. Natl. Acad. Sci. USA94:4312-4317 (1997).
Forman, et al., “Unique in Response Pathways Are Established by Allosteric Interactions among Nuclear Hormone Receptors”Cell81:541-550 (1995).
Gonzalez, et al., “Complete cDNA and Protein Sequence of a Pregnenolone 16α-Carbonitrile-induced Cytochrome P-450”The Journal of Biological Chemistry260 (12):7435-7441 (1985).
Gonzalez, et al., “Pregnenolone 16α-Carbonitrile-Inducible P-450 Gene Family: Gene Conversion and Differential Regulation”Molecular and Cellular Biology6 (8):2969-2976 (1986).
Gottlicher, et al., “Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor”Proc. Natl. Acad. Sci. USA89:4653-4657 (1992).
Hankinson, O., “The Aryl Hydrocarbon Receptor Complex”Ann. Rev. Pharmacol. Toxicol.35:307-340 (1995).
Hardwick, et al., “Cloning of DNA Complementary to Cytochrome P-450 Induced by Pregnenolone-16α-carbonitrile”The Journal of Biological Chemistry258 (16):10182-10186 (1983).
Henikoff and Henikoff, “Amino acid substitution matrices from protein blocks”Proc. Natl. Acad. Sci. USA10915-10919 (1992).
Heuman, et al., “Immunochemical Evidence for Induction of a Common Form of Hepatic Cytochrome P-450 in Rats Treated with Pregnenolone-16α-carbonitrile or other Steroidal or Non-Steroidal Agents”Molecular Pharmacology21:753-760 (1982).
Hollenberg, et al., “Primary structure and expression of a functional human glucocorticoid receptor cDNA”Nature318 (6047):635-641 (1985).
Jonat, et al., “Antitumor Promotion and Antiinflammation: Down-Modulation of AP-1 (Fos/Jun) Activity by Glucocorticoid Hormone”Cell62:1189-1204 (1990).
Juchau, M.R., “Substrate Specificities and Functions of the P450 Cytochromes”Life Sciences47:2385-2394 (1990).
Ladias and Karathanasis, “Regulation of the Apolipoprotein AI Gene by ARP-1, a Novel Member of the Steroid Receptor Superfamily”Science251:561-565 (1991).
Mangelsdorf and Evans, “The RXR Heterodimers and Orphan Receptors”Cell83:841-850 (1995).
Mangelsdorf, et al., “The Nuclear Receptor Superfamily: The Second Decade”Cell83:835-839 (1995).
Miyata, et al., “Transcriptional Elements Directing a Liver-Specific Expression of P450/6βA (CYP3A2) Gene-Encoding Testosterone 6β-Hydroxylase”Archives of Biochemistry and Biophysics318 (1):71-79 (1995).
Nebert and Gonzalez, P450 Genes: Structure, Evolution, and RegulationAnn. Rev. Biochem.56:945-993 (1987).
Needleman and Wunsch, “A General Method Applicable to the Search for Similarities in the Amino Acid Sequence of Two Proteins”J. Mol. Biol.48:443-453 (1970).
O'Malley and Conneely, “Orphan Receptors: In Search of Unifying Hypothesis for Activation”Molecular Endocrinology6 (9):1359-1361 (1992).
Ogura and Evans, A retinoic-triggered cascade ofHOXB1gene activationProc. Natl. Acad. Sci. USA92:387-391 (1995).
Perlmann et al., “Determination for selective RAR and TR recognition of direct repeat HREs”Genes Dev.7:1411-1422 (1993).
Quattrochi, et al., “A Novelcis-Acting Element in a Liver Cytochrome P450 3A Gene Confers Synergistic Induction by Glucocorticoids plus Antiglucocorticoids”The Journal of Biological Chemistry270 (48):28917-28923 (1995).
Russell and Wilson, “Steroid 5α-Reductase: Two Genes/Two Enzymes”Ann. Rev. Biochem.63:25-61 (1994).
Scheutz and Guzelian, “Induction of Cytochrome P-450 by Glucocorticoids in Rat Liver I. Evidence That Glucocorticoids Regulate Induction of Cytochrome p-450 by a Nonclassical Receptor Mechanism”The Journal of Biological Chemistry259 (3):2007-2012 (1984).
Scheutz, et al., “Induction of Cytochrome P-450 by Glucocorticoids in Rat Liver I. Evidence That Glucocorticoids and Pregnenolone 16β-Carbonitrile RegulateDe NovoSynthesis of a Common Form of Cytochrome P-450 in Cultures of Adult Rat Hepatocytes and in the Liver in Vivo”The Journal of Biological Chemistry259 (3):1999-2006 (1984).
Schuele, et al., “Functio

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