Modulation of metabolism of steroids and xenobiotics

Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C435S007800, C435S015000, C435S018000

Reexamination Certificate

active

07413853

ABSTRACT:
In accordance with the present invention, there are provided methods for modulating Phase II conjugating enzymes such as, for example, UGTs. Phase II conjugating enzymes such as UGTs function in concert with Phase I monooxygenase enzymes such as cytochrome P450 enzymes (CYPs) to eliminate steroids and xenobiotics. Nuclear receptors SXR/PXR and CAR are xenosensors regulating expression of CYP genes such as CYP3A and 2B. The ability of this group of receptors to regulate expression of UGT in response to steroids and/or xenobiotics provides novel approaches for direct regulation/activation of a glucuronidation pathway, thereby providing methods to achieve physiologic homeostasis with respect to steroids and/or xenobiotics. SXR/PXR and CAR regulation/activation of UGT represents the first evidence of receptors that can transduce/transactivate both Phase I and Phase II adaptive hepatic response. In another aspect, the present invention also provides transgenic rodents expressing one or more of SXR, CAR or PXR.

REFERENCES:
patent: 5589504 (1996-12-01), Dannenberg et al.
patent: 6287834 (2001-09-01), Belanger et al.
patent: 6395481 (2002-05-01), Di Rienzo et al.
patent: 2003/0223993 (2003-12-01), Evans et al.
Carrier et al., Isolation and characterization of the human UGT2B7 gene. Biochem Biophys Res Commun. Jun. 7, 2000;272(2):616-21.
Wen Xie et al., Orphan nuclear receptors: the exotics of xenobiotics. J. Biol. Chem., vol. 276, Issue 41, 37739-37742, Oct. 12, 2001.
Barwick et al., Trans-species gene transfer for analysis of glucocorticoid-inducible transcriptional activation of transiently expressed human CYP3A4 and rabbit CYP3A6 in primary cultures of adult rat and rabbit hepatocytes. Mol Pharmacol. Jul. 1996;50(1):10-6.
Roy-Chowdhury J, et al., Nuclear receptors orchestrate detoxification pathways.Dev Cell. May 2003;4(5):607-8.
Baes et al., A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements, Mol. Cell Biol., 14:1544-1552, 1994.
Barwick et al., Trans-species gene transfer for analysis of glucocorticoid-inducible transcriptional activation of transiently expressed human CYP3A4 and rabbit CYP3A6 in primary cultures of adult rat and rabbit hepatocytes.Mol. Pharmacol. 50:10-16, 1996.
Beaune et al., Isolation and sequence determination of a cDNA clone related to human cytochrome P-450 nifedipine oxidase.Proc. Natl. Acad. Sci. USA83:8064-8068, 1986.
Borcherding et al., Update on rifampin drug interactions II.Arch. Intern. Med. 152:711-716, 1992.
Burger et al., Paradoxical transcriptional activation of rat liver cytochrome P-450 3A1 by dexamethasone and the antiglucocorticoid pregnenolone 16$\alpha$-carbonitrile : Analysis by transient transfection into primary monolayer cultures of adult rat hepatocytes.Proc. Natl. Acad. Sci. USA 89:2145-2149, 1992.
Denison and Whitlock Jr., Xenobiotic-inducible transcription of cytochrome P450 genes.J. Biol. Chem. 270:18175-18178.
Elayadi & Corey, Application of PNA and LNA oligomers to chemotherapy.Curr. Opin. Invest. Drugs 2:558-561, 2001.
Fernandez-Salguero and Gonzalez, The CYP2A gene subfamily: species differences, regulation, catalytic activities and role in chemical carcinogenesis.Pharmacogenetics 5:S123-128, 1995.
Gonzalez et al., Pregnenolone 16α Carbonitrile-inducible P-450 gene family: Gene conversion and differential regulation.Mol. Cell. Biol. 6:2969-2976, 1986.
Gonzalez, Human cytochromes P450 : problems and prospects.Trends Pharmacol. Sci. 13:346-352, 1992.
Hankinson, The Aryl hydrocarbon receptor complex.Ann. Rev. Pharmacol. Toxicol. 35:307-340, 1995.
Herbert et al., Pharmacokinetics and drug disposition.Clin. Pharmacol. Ther. 52:453-457, 1992.
Kolars et al., Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes.J. Clin. Invest. 90:1871-1878, 1992.
Kolars et al., CYP3A gene expression in human gut epithelium.Pharmacogenetics 4:247-259, 1994.
Lehmann et al., The human orphan nuclear receptor PX Ris activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.J. Clin. Invest. 102:1016-1023, 1998.
Mackenzie et al., The UDP glycosyltransferase gene superfamily : recommended nomenclature update based on evolutionary divergence.Pharmacogenetics 7:255-269, 1997.
Molowa et al., Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver.Proc. Natl. Acad. Sci. USA83:5311-5315, 1986.
Neuschwander-Tetri et al, Troglitazone-induced hepatic failure leading to liver transplantation.Ann. Intern. Med. 129:38-41, 1998.
Rendic and Di Carlo, Human Cytochrome P40 enzymes: A status report summarizing their reactions, substrates, inducers, and inhibitors.Drug. Metab. Rev. 29:413-580, 1997.
Schuetz and Guzelian, Induction of cytochrome P-450 by glucocorticoids in rat liver.J. Biol. Chem. 259:2007-2012, 1984.
Shibuya et al., An autopsy case of troglitazone-induced fulminant hepatitis.Diabetes Care 21:2140-2143, 1998.
Spiegelman, PPAR-y: Adipogenic regulator and thiazolidinedione receptor.Diabetes 47:507-514, 1998.
Tukey and Strassburg, Human UDP-Glucuronosyltransferases: Metabolism, Expression and Disease.Annu. Rev. Pharmacol. Toxicol. 40:581-616, 2000.
Wilson and Wahli, Peroxisome proliferators-activated receptor agonists.Curr. Opin. Chem Biol. 1:235-241, 1997.
Wrighton et al., Demonstration in multiple species of inducible hepatic cytochromes P-450 and their mRNAs related to the glucocorticoid-inducible cytochrome P-450 of the rat.Mol. Pharmacol. 28:312-321, 1985.
Xie et al., An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. PNAS, 98 : 3375-3380, 2001.
Xi et al., Humanized xenobiotic response in mice expressing nuclear receptor SXR. Natuire, 406 :435-439, 2000.
Xie et al., Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PX Rand CAR. Genes and Development, 14 :3014-3023, 2000.
International Search Report for International Application No. PCT/US02/21800.

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Modulation of metabolism of steroids and xenobiotics does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Modulation of metabolism of steroids and xenobiotics, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Modulation of metabolism of steroids and xenobiotics will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-3998927

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.