A double transgenic mouse model expressing human pregnane X receptor and cytochrome P450 3A4.
Cytochrome P450 3A4 (CYP3A4), the most abundant human cytochrome P450 in liver, participates in the metabolism of approximately 50% of clinically used drugs. The pregnane X receptor (PXR), a member of the nuclear receptor superfamily, is the major activator of CYP3A4 transcription. However, because of species differences in response to PXR ligands, it is problematic to use rodents to assess CYP3A4 regulation and function. The generation of double transgenic mice expressing human PXR and CYP3A4 (TgCYP3A4/hPXR) would provide a solution to this problem. In the current study, a TgCYP3A4/hPXR mouse model was generated by bacterial artificial chromosome transgenesis in Pxr-null mice. In TgCYP3A4/hPXR mice, CYP3A4 was strongly induced by rifampicin, a human-specific PXR ligand, but not by pregnenolone 16alpha-carbonitrile, a rodent-specific PXR ligand. Consistent with CYP3A expression, hepatic CYP3A activity increased approximately 5-fold in TgCYP3A4/hPXR mice pretreated with rifampicin. Most antihuman immunodeficiency virus protease inhibitors are CYP3A substrates and their interactions with rifamycins are a source of major concern in patients coinfected with human immunodeficiency virus and Mycobacterium tuberculosis. By using TgCYP3A4/hPXR mice, human PXR-CYP3A4-mediated rifampicin-protease inhibitor interactions were recapitulated, as the metabolic stability of amprenavir, nelfinavir, and saquinavir decreased 52, 53, and 99%, respectively, in the liver microsomes of TgCYP3A4/hPXR mice pretreated with rifampicin. In vivo, rifampicin pretreatment resulted in an approximately 80% decrease in the area under the serum amprenavir concentration-time curve in TgCYP3A4/hPXR mice. These results suggest that the TgCYP3A4/hPXR mouse model could serve as a useful tool for studies on CYP3A4 transcription and function in vivo.
Ma
Xiaochao
X
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Cheung
Connie
C
Krausz
Kristopher W
KW
Shah
Yatrik M
YM
Wang
Ting
T
Idle
Jeffrey R
JR
Gonzalez
Frank J
FJ
D000818:Animals; D002219:Carbamates / Q000378:metabolism / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D005663:Furans; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000502:physiology; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D019888:Nelfinavir / Q000378:metabolism; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011987:Receptors, Steroid / Q000235:genetics*; D012293:Rifampin / Q000494:pharmacology; D019258:Saquinavir / Q000378:metabolism; D012727:Sex Characteristics; D013449:Sulfonamides / Q000378:metabolism / Q000493:pharmacokinetics; D008565:Membrane Proteins
D002219:Carbamates; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D005663:Furans; D017320:HIV Protease Inhibitors; D007654:Ketoconazole; D019888:Nelfinavir; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile; D011987:Receptors, Steroid; D012293:Rifampin; D019258:Saquinavir; D013449:Sulfonamides; C095108:amprenavir; C510163:CYP3A4 protein, human; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):223-8
12509506
Curr Drug Metab. 2007 Feb;8(2):185-94
17305497
Biochem Pharmacol. 1995 Nov 27;50(11):1841-50
8615863
Nature. 2000 Jul 27;406(6794):435-9
10935643
Clin Pharmacol Ther. 1990 Oct;48(4):365-74
2121408
Drug Metab Dispos. 2003 May;31(5):548-58
12695342
J Biol Chem. 1987 Oct 5;262(28):13534-7
3654629
Drugs. 2006;66(18):2299-308
17181373
Curr Drug Metab. 2004 Dec;5(6):483-505
15578943
Drug Metab Dispos. 2003 Aug;31(8):1054-64
12867495
J Pharmacol Exp Ther. 1994 Oct;271(1):549-56
7965755
Clin Pharmacokinet. 2003;42(9):819-50
12882588
J Clin Invest. 1998 Sep 1;102(5):1016-23
9727070
Biochem Biophys Res Commun. 2001 Mar;281(5):1349-55
11243885
Drug Metab Dispos. 2007 Feb;35(2):194-200
17093002
Pharmacogenomics. 2004 Apr;5(3):243-72
15102541
Hepatology. 2003 Oct;38(4):978-88
14512885
J Antimicrob Chemother. 2007 Apr;59(4):690-7
17307771
Antimicrob Agents Chemother. 2001 Feb;45(2):502-8
11158747
Annu Rev Pharmacol Toxicol. 1999;39:1-17
10331074
Curr Drug Metab. 2005 Aug;6(4):357-67
16101574
J Mass Spectrom. 2003 Feb;38(2):157-66
12577282
Trop Doct. 2006 Apr;36(2):73-9
16611437
Acta Pharmacol Sin. 2001 Oct;22(10):944-8
11749780
J Biol Chem. 1999 Aug 20;274(34):23963-8
10446164
Drug Metab Dispos. 2000 Sep;28(9):1051-7
10950848
Biochemistry. 1990 Dec 25;29(51):11280-92
2271712
Annu Rev Pharmacol Toxicol. 2006;46:41-64
16402898
Mol Pharmacol. 2003 Jul;64(1):42-50
12815159
Drug Metab Dispos. 2004 Feb;32(2):163-7
14744936
Endocrinology. 2005 Jul;146(7):2911-9
15817670
J Biol Chem. 2003 Nov 14;278(46):45062-71
12923173
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3369-74
11248085
J Pharmacol Exp Ther. 2006 Mar;316(3):1328-34
16291874
Pharmacogenetics. 2001 Mar;11(2):111-21
11266076
Protein Expr Purif. 2002 Apr;24(3):329-37
11922748
Mol Endocrinol. 2000 Jan;14(1):27-39
10628745