title: Relationship between hepatic phenotype and changes in gene expression in cytochrome P450 reductase (POR) null mice.
abstract: Cytochrome P450 reductase is the unique electron donor for microsomal cytochrome P450s; these enzymes play a major role in the metabolism of endogenous and xenobiotic compounds. In mice with a liver-specific deletion of cytochrome P450 reductase, hepatic cytochrome P450 activity is ablated, with consequent changes in bile acid and lipid homoeostasis. In order to gain insights into the metabolic changes resulting from this phenotype, we have analysed changes in hepatic mRNA expression using microarray analysis and real-time PCR. In parallel with the perturbations in bile acid levels, changes in the expression of key enzymes involved in cholesterol and lipid homoeostasis were observed in hepatic cytochrome P450 reductase null mice. This was characterized by a reduced expression of Cyp7b1, and elevation of Cyp7a1 and Cyp8b1 expression. The levels of mRNAs for other cytochrome P450 genes, including Cyp2b10, Cyp2c29, Cyp3a11 and Cyp3a16, were increased, demonstrating that endogenous factors play a role in regulating the expression of these proteins and that the increases are due, at least in part, to altered levels of transcripts. In addition, levels of mRNAs encoding genes involved in glycolysis and lipid transport were also increased; the latter may provide an explanation for the increased hepatic lipid content observed in the hepatic null mice. Serum testosterone and oestradiol levels were lowered, accompanied by significantly decreased expression of Hsd3b2 (3beta-hydroxy-Delta5-steroid dehydrogenase-2), Hsd3b5 (3beta-hydroxy-Delta5-steroid dehydrogenase-5) and Hsd11b1 (11beta-hydroxysteroid dehydrogenase type 1), key enzymes in steroid hormone metabolism. These microarray data provide important insights into the control of metabolic pathways by the cytochrome system.
authors.affiliation: Biomedical Research Centre, Level 5, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.
authors.forename: Xiu Jun
authors.initials: XJ
authors.lastname: Wang
authors.forename: Mark
authors.initials: M
authors.lastname: Chamberlain
authors.forename: Olga
authors.initials: O
authors.lastname: Vassieva
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Henderson
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism; D002784:Cholesterol / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000235:genetics; D006728:Hormones / Q000378:metabolism; D007109:Immunity / Q000235:genetics; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009251:NADPH-Ferrihemoprotein Reductase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D006728:Hormones; D012333:RNA, Messenger; D002784:Cholesterol; D009251:NADPH-Ferrihemoprotein Reductase
references.citation: Mol Aspects Med. 1999 Feb-Apr;20(1-2):12-24, 25-137
references.pmid: 10575648
references.citation: Prog Lipid Res. 2004 Mar;43(2):91-104
references.pmid: 14654089
references.citation: Genes Dev. 2000 Apr 15;14(8):963-80
references.pmid: 10783168
references.citation: Mol Cell. 2000 Sep;6(3):507-15
references.pmid: 11030331
references.citation: Mol Cell. 2000 Sep;6(3):517-26
references.pmid: 11030332
references.citation: Cell. 2000 Sep 15;102(6):731-44
references.pmid: 11030617
references.citation: Annu Rev Cell Dev Biol. 2000;16:459-81
references.pmid: 11031244
references.citation: J Biol Chem. 2000 Dec 29;275(52):41087-91
references.pmid: 11022049
references.citation: Front Biosci. 2001 Mar 1;6:D388-405
references.pmid: 11229871
references.citation: J Biol Chem. 2001 Nov 23;276(47):43915-23
references.pmid: 11522786
references.citation: Biochim Biophys Acta. 2003 Feb 17;1619(3):223-34
references.pmid: 12573481
references.citation: Pharmacol Rev. 2003 Dec;55(4):649-73
references.pmid: 14657421
references.citation: J Biol Chem. 2004 Jan 23;279(4):2480-9
references.pmid: 14583614
references.citation: Diabetes. 2004 Apr;53(4):1020-9
references.pmid: 15047617
references.citation: Mol Endocrinol. 2004 Jul;18(7):1589-98
references.pmid: 14988430
references.citation: J Biol Chem. 1975 Feb 25;250(4):1571-9
references.pmid: 234459
references.citation: J Biol Chem. 1979 Sep 25;254(18):8976-81
references.pmid: 113406
references.citation: J Biol Chem. 1981 Oct 10;256(19):10066-72
references.pmid: 6792195
references.citation: J Biol Chem. 1989 May 5;264(13):7584-9
references.pmid: 2708380
references.citation: Cell. 1995 Dec 1;83(5):803-12
references.pmid: 8521497
references.citation: Eur J Biochem. 1995 Dec 1;234(2):390-6
references.pmid: 8536680
references.citation: J Biol Chem. 1996 Jul 26;271(30):18017-23
references.pmid: 8663429
references.citation: J Biol Chem. 1996 Jul 26;271(30):18024-31
references.pmid: 8663430
references.citation: J Lipid Res. 1996 Apr;37(4):693-707
references.pmid: 8732771
references.citation: EMBO J. 1996 Oct 1;15(19):5336-48
references.pmid: 8895578
references.citation: Annu Rev Pharmacol Toxicol. 1997;37:517-54
references.pmid: 9131263
references.citation: Mol Pharmacol. 1998 Apr;53(4):597-601
references.pmid: 9547348
references.citation: Cell. 1998 May 29;93(5):693-704
references.pmid: 9630215
references.citation: Biochem Biophys Res Commun. 1998 Jun 18;247(2):255-60
references.pmid: 9642112
references.citation: J Biol Chem. 1998 Dec 25;273(52):35299-306
references.pmid: 9857071
references.citation: Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):266-71
references.pmid: 9874807
references.citation: Curr Opin Lipidol. 1999 Apr;10(2):143-50
references.pmid: 10327282
references.citation: Science. 1999 May 21;284(5418):1362-5
references.pmid: 10334992
references.citation: Science. 1999 May 21;284(5418):1365-8
references.pmid: 10334993
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11041-8
references.pmid: 10500120
references.citation: J Biol Chem. 2001 Dec 28;276(52):49066-76
references.pmid: 11551957
references.citation: Mol Pharmacol. 2002 Jan;61(1):1-6
references.pmid: 11752199
references.citation: J Cell Biochem. 2002;85(3):651-61
references.pmid: 11968005
references.citation: J Biol Chem. 2002 Jun 21;277(25):22710-7
references.pmid: 11932260
references.citation: Endocr Rev. 2002 Aug;23(4):443-63
references.pmid: 12202460
references.citation: Antioxid Redox Signal. 2002 Aug;4(4):593-602
references.pmid: 12230871
references.citation: Lancet. 2002 Oct 12;360(9340):1155-62
references.pmid: 12387968
references.citation: Biochim Biophys Acta. 2003 Feb 17;1619(3):235-8
references.pmid: 12573482
references.citation: Am J Physiol Gastrointest Liver Physiol. 2003 Mar;284(3):G349-56
references.pmid: 12576301
references.citation: Biochim Biophys Acta. 2003 Mar 17;1631(2):177-87
references.pmid: 12633684
references.citation: J Biol Chem. 2003 Apr 11;278(15):13480-6
references.pmid: 12566435
references.citation: EHP Toxicogenomics. 2003 Jan;111(1T):45-51
references.pmid: 12735109
references.citation: J Biol Chem. 2003 Jul 11;278(28):25895-901
references.pmid: 12697746
references.citation: Annu Rev Biochem. 2003;72:137-74
references.pmid: 12543708
references.citation: Arch Biochem Biophys. 2000 Feb 15;374(2):293-8
references.pmid: 10666310