The transcriptional regulation of the human CYP2C genes.
In humans, four members of the CYP2C subfamily (CYP2C8, CYP2C9, CYP2C18, and CYP2C19) metabolize more than 20% of all therapeutic drugs as well as a number of endogenous compounds. The CYP2C enzymes are found predominantly in the liver, where they comprise approximately 20% of the total cytochrome P450. A variety of xenobiotics such as phenobarbital, rifampicin, and hyperforin have been shown to induce the transcriptional expression of CYP2C genes in primary human hepatocytes and to increase the metabolism of CYP2C substrates in vivo in man. This induction can result in drug-drug interactions, drug tolerance, and therapeutic failure. Several drug-activated nuclear receptors including CAR, PXR, VDR, and GR recognize drug responsive elements within the 5' flanking promoter region of CYP2C genes to mediate the transcriptional upregulation of these genes in response to xenobiotics and steroids. Other nuclear receptors and transcriptional factors including HNF4alpha, HNF3gamma, C/EBPalpha and more recently RORs, have been reported to regulate the constitutive expression of CYP2C genes in liver. The maximum transcriptional induction of CYP2C genes appears to be achieved through a coordinative cross-talk between drug responsive nuclear receptors, hepatic factors, and coactivators. The transcriptional regulatory mechanisms of the expression of CYP2C genes in extrahepatic tissues has received less study, but these may be altered by perturbations from pathological conditions such as ischemia as well as some of the receptors mentioned above.
Chen
Yuping
Y
Laboratory of Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Goldstein
Joyce A
JA
D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008099:Liver / Q000201:enzymology
C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System
J Clin Invest. 2006 Jun;116(6):1696-702
16691295
Biochem Pharmacol. 1996 Aug 9;52(3):497-504
8687505
Adv Dev Biol. 2006;16:313-355
18418469
J Clin Invest. 2008 Sep;118(9):3228-39
18677425
J Acquir Immune Defic Syndr. 2004 Aug 15;36(5):1034-40
15247556
Pharm Res. 2005 Jan;22(1):71-8
15771232
Pharmacogenetics. 1996 Aug;6(4):341-9
8873220
Drug Metab Dispos. 2004 May;32(5):512-8
15100173
Circ Res. 2001 Oct 26;89(9):753-62
11679404
Clin Pharmacol Ther. 2006 Jan;79(1):103-13
16413245
Drug Metab Dispos. 2007 Apr;35(4):682-8
17220242
Cardiovasc Res. 2002 Jun;54(3):669-75
12031713
Mol Cell Biol. 2001 Apr;21(8):2838-46
11283262
J Biochem Mol Toxicol. 1999;13(6):289-95
10487415
Pharmacogenetics. 2004 Jan;14(1):1-18
15128046
Mol Pharmacol. 2004 May;65(5):1148-58
15102943
J Biol Chem. 2004 Apr 2;279(14):13506-13
14726529
Eur J Clin Pharmacol. 1975 Dec 19;9(2-3):219-27
1233266
J Biol Chem. 1994 Jun 3;269(22):15419-22
8195181
Br J Clin Pharmacol. 2006 Jan;61(1):70-8
16390353
Nat Med. 2001 May;7(5):584-90
11329060
Eur J Clin Pharmacol. 2005 Jul;61(5-6):341-6
15983826
J Physiol. 2003 Jan 1;546(Pt 1):307-14
12509498
Obes Res. 2004 Aug;12(8):1278-89
15340111
Drug Metab Dispos. 2007 Oct;35(10):1853-9
17639026
Pharmacogenetics. 2002 Apr;12(3):251-63
11927841
Biochemistry. 1995 Jun 27;34(25):8028-36
7794915
Mol Pharmacol. 2006 Dec;70(6):1925-34
16988011
Clin Pharmacol Ther. 1998 Mar;63(3):316-23
9542475
Clin Pharmacokinet. 2003;42(9):819-50
12882588
Drug Metab Dispos. 2001 Mar;29(3):242-51
11181490
J Biol Chem. 2001 Sep 7;276(36):33309-12
11466304
Biochim Biophys Acta. 2003 Feb 17;1619(3):332-9
12573493
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):1045-50
17213310
Clin Pharmacol Ther. 2004 Sep;76(3):239-49
15371985
J Biol Chem. 2002 Jan 4;277(1):209-17
11679585
Mol Pharmacol. 2008 Sep;74(3):913-23
18552123
Drug Metab Dispos. 2006 May;34(5):880-6
16467132
J Biol Chem. 2006 May 26;281(21):14683-90
16574644
J Biol Chem. 1992 Aug 25;267(24):17333-8
1324931
Hypertension. 2001 Dec 1;38(6):1427-32
11751730
J Clin Pharmacol. 2004 Jun;44(6):577-81
15145964
J Pharmacol Exp Ther. 2004 Feb;308(2):495-501
14600250
Mol Pharmacol. 2000 Dec;58(6):1441-50
11093784
Hypertension. 2006 Mar;47(3):557-62
16415373
J Pharmacol Exp Ther. 2009 Apr;329(1):192-201
19164466
Clin Pharmacol Ther. 2004 Mar;75(3):191-7
15001970
Biochemistry. 2003 Jun 3;42(21):6363-9
12767217
Arterioscler Thromb Vasc Biol. 2008 Jun;28(6):1123-9
18340006
Clin Pharmacokinet. 1996 Sep;31(3):198-214
8877250
Clin Cancer Res. 2005 Oct 1;11(19 Pt 1):6972-9
16203790
Pharmacogenetics. 2003 Sep;13(9):565-75
12972955
Br J Clin Pharmacol. 2001 Oct;52(4):349-55
11678778
N Engl J Med. 2009 Jan 22;360(4):354-62
19106084
Mol Pharmacol. 2002 Sep;62(3):737-46
12181452
Can J Physiol Pharmacol. 2006 Jan;84(1):15-20
16845886
Mol Pharmacol. 1994 Oct;46(4):594-8
7969038
Oral Dis. 2009 Sep;15(6):382-7
19413677
Hypertension. 2000 Aug;36(2):270-5
10948089
Drug Metab Dispos. 2007 Sep;35(9):1687-93
17576808
Drug Metab Dispos. 2003 Apr;31(4):421-31
12642468
Arch Biochem Biophys. 2004 Jun 1;426(1):63-72
15130783
Mol Pharmacol. 2004 Jun;65(6):1397-404
15155833
Mol Pharmacol. 2005 Jun;67(6):1954-65
15761118
J Pharmacol Exp Ther. 2001 Dec;299(3):849-57
11714868
Biochem Biophys Res Commun. 2000 Aug 11;274(3):707-13
10924340
Hypertension. 2003 Oct;42(4):594-9
12939236
J Biol Chem. 2005 Feb 11;280(6):4367-73
15572372
J Cardiovasc Pharmacol. 2007 May;49(5):306-15
17513950
Am J Pathol. 2004 Feb;164(2):521-32
14742258
Pediatr Res. 2000 May;47(5):677-83
10813596
Clin Pharmacol Ther. 2004 Mar;75(3):157-62
15001966
J Histochem Cytochem. 2004 Apr;52(4):447-54
15033996
Drug Metab Dispos. 2006 Jun;34(6):1012-8
16540586
Pharmacogenetics. 2001 Oct;11(7):597-607
11668219
Mol Pharmacol. 2006 Nov;70(5):1681-92
16882880
Mol Pharmacol. 2005 Sep;68(3):747-57
15933212
Clin Pharmacol Ther. 1987 Oct;42(4):388-94
3665337
Mol Pharmacol. 2000 Aug;58(2):361-72
10908304
Drug Metab Dispos. 2004 Dec;32(12):1370-6
15333513
Am J Physiol Cell Physiol. 2008 Nov;295(5):C1292-301
18787075
J Biol Chem. 2002 Jul 12;277(28):25125-32
11991950
Basic Clin Pharmacol Toxicol. 2004 Jul;95(1):2-8
15245569
Br J Pharmacol. 2008 Apr;153(7):1579-86
18204476
Hepatology. 2003 Jun;37(6):1375-84
12774017
Science. 2002 May 17;296(5571):1313-6
12016314
Drug Metab Dispos. 2007 Sep;35(9):1700-10
17576804
Hepatology. 2001 Mar;33(3):668-75
11230748
Pharmacogenomics. 2008 May;9(5):511-26
18466099
Cancer Chemother Pharmacol. 2005 Sep;56(3):248-54
15856231
Physiol Genomics. 2007 Oct 22;31(2):281-94
17666523
J Biol Chem. 2006 Sep 8;281(36):26540-51
16825189
Mol Pharmacol. 2000 Dec;58(6):1341-8
11093772
Pharmacol Rev. 2003 Dec;55(4):649-73
14657421
Hepatology. 2004 Oct;40(4):951-60
15382119
J Pharmacol Exp Ther. 2005 Sep;314(3):1125-33
15919766
Clin Pharmacol Ther. 2008 Feb;83(2):312-21
17653141
Biochim Biophys Acta. 2003 Feb 17;1619(3):223-34
12573481
Toxicol Lett. 2005 Dec 15;159(3):203-11
16188404
Br J Clin Pharmacol. 2005 Feb;59(2):199-206
15676042
Biochem Pharmacol. 1998 Mar 15;55(6):825-30
9586955
Arch Biochem Biophys. 1995 Sep 10;322(1):76-86
7574697
Cancer Res. 1997 May 15;57(10):1946-54
9157990
Drug Metab Dispos. 2008 May;36(5):955-62
18276835
Drug Metab Dispos. 2006 Dec;34(12):2003-10
16936065
Biochem J. 2007 Feb 1;401(3):735-41
17032173
J Clin Pharmacol. 2004 Mar;44(3):215-23
14973304
Drug Metab Dispos. 2001 Oct;29(10):1325-31
11560876
Kidney Int. 2007 Sep;72(6):683-9
17597703
Clin Pharmacol Ther. 1998 Aug;64(2):160-7
9728896
J Cell Sci. 2005 Dec 1;118(Pt 23):5489-98
16291720
Pharmacogenet Genomics. 2007 Nov;17(11):907-18
18075461
Oncol Res. 1999;11(11-12):523-8
10905564
Am J Physiol Renal Physiol. 2009 Mar;296(3):F556-63
19129258
Biochem Biophys Res Commun. 1993 Jul 15;194(1):194-201
8333835
J Pharmacol Sci. 2008 Sep;108(1):79-88
18776712
Trends Pharmacol Sci. 2007 Sep;28(9):448-52
17764757
Mol Pharmacol. 2003 Mar;63(3):524-31
12606758
Clin Pharmacol Ther. 2001 Jun;69(6):400-6
11406737
Circ Res. 2001 Jan 19;88(1):44-51
11139472
Br J Clin Pharmacol. 1990 Sep;30(3):471-5
2223426
J Biol Chem. 2003 May 9;278(19):17277-83
12611900
Nat Med. 2003 Feb;9(2):220-4
12514743
Pharmacotherapy. 2008 Jul;28(7):945-9
18576910
Drug Metab Dispos. 2007 Jul;35(7):1126-34
17431031
Drug Metab Dispos. 2005 Jul;33(7):924-9
15802384
Drug Metab Pharmacokinet. 2007 Aug;22(4):287-98
17827783
FEBS Lett. 1998 Jul 17;431(2):227-30
9708908
Br J Clin Pharmacol. 1998 Jan;45(1):27-9
9489590
Mol Pharmacol. 2003 Aug;64(2):316-24
12869636
J Pharmacol Exp Ther. 2002 Aug;302(2):475-82
12130704
Br J Clin Pharmacol. 2004 May;57(5):592-9
15089812