Regulation of Hepatic Drug Metabolism: Role of the Nuclear Receptors PXR and CAR

ABSTRACT

Recent advances in the molecular biology of nuclear receptors have revealed that the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are able to act as sensors for lipophilic xenobiotics, including therapeutic drugs. These receptors in turn regulate enzymes and transporters involved in drug metabolism and disposition in an adaptive fashion. An unexpected finding was that the PXR was able to recognize bile acids; transgenic animals lacking this receptor are at increased risk of bile acid-induced liver injury. These findings provide new insights into hepatic drug metabolism as well as mechanisms regulating cholesterol and bile acid homeostasis.

KEYWORDS

Cytochrome P450 - bile acids - drug disposition - drug metabolism - nuclear receptor - pregnane X receptor - constitutive androstane receptor

REFERENCES

• 1 Remmer H. Drug tolerance. In: Monga JL, De Reuck AVS, eds. Ciba Foundation Symposium on Enzymes and Drug Action London: Churchill 1962: 276-298
• 2 Conney A H. Pharmacological implications of microsomal enzyme induction.  Pharmacol Rev . 1967;  19 317-366
• 3 Nelson D R, Koymans L, Kamataki T. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature.  Pharmacogenetics . 1996;  6 1-42
• 4 Gonzalez F J, Gelboin H V. Human cytochromes P450: evolution and cDNA-directed expression.  Environ Health Perspect . 1992;  98 81-85
• 5 Shimada T, Yamazaki H, Mimura M. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians.  J Pharmacol Exp Ther . 1994;  270 414-423
• 6 Brian W R, Sari M A, Iwasaki M. Catalytic activities of human liver cytochrome P-450 IIIA4 expressed in Saccharomyces cerevisiae Biochemistry .  1990;  29 11280-11292
• 7 Nebert D W, Gonzalez F J. P450 genes: structure, evolution, and regulation.  Annu Rev Biochem . 1987;  56 945-993
• 8 Maurel P. The CYP3A family. In: Ioannides C, ed. Cytochromes P450: Metabolic and Toxicological Aspects Boca Raton, FL: CRC Press 1996: 241-270
• 9 Kolars J C, Lown K S, Schmiedlin-Ren P. CYP3A expression in human gut epithelium.  Pharmacogenetics . 1994;  4 247-259
• 10 Huang Z, Fasco M J, Figge H L. Expression of cytochromes P450 in human breast.  Drug Metab Dispos . 1996;  24 899-905
• 11 Schuetz J D, Beach D L, Guzelian P S. Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver.  Pharmacogenetics . 1994;  4 11-20
• 12 Lacroix D, Sonnier M, Moncion A. Expression of CYP3A in the human liver-evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth.  Eur J Biochem . 1997;  247 625-634
• 13 Itoh S, Satoh M, Abe Y. A novel form of mouse cytochrome P450 3A (Cyp3A-16). Its cDNA cloning and expression in fetal liver.  Eur J Biochem . 1994;  226 877-882
• 14 Denison M S, Whitlock Jr P J. Xenobiotic-inducible transcription of cytochrome P450 genes.  J Biol Chem . 1995;  270 18175-18178
• 15 Michalets E L. Update: clinically significant cytochrome P-450 drug interactions.  Pharmacotherapy . 1998;  18 84-112
• 16 Whitlock Jr P J, Chichester C H, Bedgood R M. Induction of drug-metabolizing enzymes by dioxin.  Drug Metab Rev . 1997;  29 1107-1127
• 17 Johnson E F, Palmer C N, Griffin K J, Hsu M H. Role of the peroxisome proliferator-activated receptor in cytochrome P450 4A gene regulation.  FASEB J . 1996;  10 1241-1248
• 18 Gonzalez F J, Fernandez-Salguero P, Lee S S. Xenobiotic receptor knockout mice.  Toxicol Lett . 1995;  82-83 117-121
• 19 Kliewer S A, Moore J T, Wade L. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway.  Cell . 1998;  92 73-82
• 20 Bertilsson G, Heidrich J, Svensson K. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction.  Proc Natl Acad Sci USA . 1998;  95 12208-12213
• 21 Blumberg B, Sabbagh Jr W, Juguilon H. SXR, a novel steroid and xenobiotic-sensing nuclear receptor.  Genes Dev . 1998;  12 3195-205
• 22 Lehmann J M, McKee D D, Watson M A. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.  J Clin Invest . 1998;  102 1016-1023
• 23 Zhang H, LeCulyse E, Liu L. Rat pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic regulation.  Arch Biochem Biophys . 1999;  368 14-22
• 24 Jones S A, Moore L B, Shenk J L. The pregnane x receptor: a promiscuous xenobiotic receptor that has diverged during evolution.  Mol Endocrinol . 2000;  14 27-39
• 25 Savas U, Wester M R, Griffin K J, Johnson E F. Rabbit pregnane X receptor is activated by rifampicin.  Drug Metab Dispos . 2000;  28 529-537
• 26 Glass C K. Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers.  Endocr Rev . 1994;  15 391-407
• 27 Mangelsdorf D J, Thummel C, Beato M. The nuclear receptor superfamily: the second decade.  Cell . 1995;  83 835-839
• 28 Bourguet W, Germain P, Gronemeyer H. Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications.  Trends Pharmacol Sci . 2000;  21 381-388
• 29 Mangelsdorf D J, Evans R M. The RXR heterodimers and orphan receptors.  Cell . 1995;  83 841-850
• 30 Giguere V. Orphan nuclear receptors: from gene to function.  Endocr Rev . 1999;  20 689-725
• 31 Blumberg B, Evans R M. Orphan nuclear receptors-new ligands and new possibilities.  Genes Dev . 1998;  12 3149-3155
• 32 Gustafsson J A. Seeking ligands for lonely orphan receptors.  Science . 1999;  284 1285-1286
• 33 Kliewer S A, Lehmann J M, Willson T M. Orphan nuclear receptors: shifting endocrinology into reverse.  Science . 1999;  284 757-760
• 34 Watkins P B, Wrighton S A, Schuetz E G. Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man.  J Clin Invest . 1987;  80 1029-1036
• 35 de Waziers I, Cugnenc P H, Yang C S. Cytochrome P450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues.  J Pharmacol Exp Ther . 1990;  253 387-394
• 36 Wrighton S A, Schuetz E G, Watkins P B. 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 . 1985;  28 312-321
• 37 Kocarek T A, Schuetz E G, Strom S C. Comparative analysis of cytochrome P4503A induction in primary cultures of rat, rabbit, and human hepatocytes.  Drug Metab Dispos . 1995;  23 415-421
• 38 Daujat M, Pichard L, Dalet C. Expression of five forms of microsomal cytochrome P-450 in primary cultures of rabbit hepatocytes treated with various classes of inducers.  Biochem Pharmacol . 1987;  36 3597-3606
• 39 Potenza C L, Pendurthi U R, Strom D K. Regulation of the rabbit cytochrome P-450 3c gene. Age-dependent expression and transcriptional activation by rifampicin.  J Biol Chem . 1989;  264 16222-16228
• 40 Goodwin B, Hodgson E, Liddle C. The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module.  Mol Pharmacol . 1999;  56 1329-1339
• 41 Pascussi J M, Jounaidi Y, Drocourt L. Evidence for the presence of a functional pregnane X receptor response element in the CYP3A7 promoter gene.  Biochem Biophys Res Commun . 1999;  260 377-381
• 42 Bertilsson G, Berkenstam A, Blomquist P. Functionally conserved xenobiotic responsive enhancer in cytochrome P450 3A7.  Biochem Biophys Res Commun . 2001;  280 139-144
• 43 Honkakoski P, Zelko I, Sueyoshi T, Negishi M. The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene.  Mol Cell Biol . 1998;  18 5652-5658
• 44 Kawamoto T, Sueyoshi T, Zelko I. Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene.  Mol Cell Biol . 1999;  19 6318-6322
• 45 Sueyoshi T, Kawamoto T, Zelko I. The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene.  J Biol Chem . 1999;  274 6043-6046
• 46 Forman B M, Tzameli I, Choi H-S. Androstane metabolites bind to and deactivate the nuclear receptor CAR-β.  Nature . 1998;  395 612-615
• 47 Moore L B, Parks D J, Jones S A. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands.  J Biol Chem . 2000;  275 15122-15127
• 48 Tzameli I, Pissios P, Schuetz E G, Moore D D. The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is as agonist ligand for the nuclear receptor CAR.  Mol Cell Biol . 2000;  20 2951-2958
• 49 Honkakoski P, Negishi M. Protein serine/threonine phosphatase inhibitors suppress phenobarbital-induced Cyp2b10 gene transcription in mouse primary hepatocytes.  Biochem J . 1998;  330 889-895
• 50 Nirodi C S, Sultana S, Ram N. Involvement of synthesis and phosphorylation of nuclear protein factors that bind to the positive cis-acting element in the transcriptional activation of the CYP2B1/B2 gene by phenobarbitone in vivo.  Arch Biochem Biophys . 1996;  331 79-86
• 51 Sidhu J S, Omiecinski C J. cAMP-associated inhibition of phenobarbital-inducible cytochrome P450 gene expression in primary rat hepatocyte culture.  J Biol Chem . 1995;  270 12762-12773
• 52 Wei P, Zhang J, Egan-Hafley M. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism.  Nature . 2000;  407 920-923
• 53 Zelko I, Sueyoshi T, Kawamoto T. The peptide near the C terminus regulates receptor CAR nuclear translocation induced by xenochemicals in mouse liver.  Mol Cell Biol . 2001;  21 2838-2846
• 54 Goodwin B, Moore L B, Stoltz C M. Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor.  Mol Pharmacol . 2001;  60 427-431
• 55 Xie W, Barwick J L, Simon C M. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR.  Genes Dev . 2000;  14 3014-3023
• 56 Smirlis D, Muangmoonchai R, Edwards M. Orphan receptor promiscuity in the induction of cytochromes P450 by xenobiotics.  J Biol Chem . 2001;  276 12822-12826
• 57 Thiebaut F, Tsuruo T, Hamada H. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues.  Proc Natl Acad Sci USA . 1987;  84 7735-7738
• 58 Greiner B, Eichelbaum M, Fritz P. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin.  J Clin Invest . 1999;  104 147-153
• 59 Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin.  J Biol Chem . 2001;  276 14581-14587
• 60 Keppler D, Konig J. Expression and localization of the conjugate export pump encoded by the MRP2 (cMRP/cMOAT) gene in liver.  FASEB J . 1997;  11 509-516
• 61 Fromm M F, Kauffmann H M, Fritz P. The effect of rifampin treatment on intestinal expression of human MRP transporters.  Am J Pathol . 2000;  157 1575-1580
• 62 Kast H R, Goodwin B, Tarr P T. Regulation of multidrug resistance-associated protein 2 (MRP2;ABCC2) by the nuclear receptors PXR, FXR, and CAR.  J Biol Chem . 2002;  277 2908-2915
• 63 Reichel C, Gao B, Van Montfoort J. Localization and function of the organic anion-transporting polypeptide Oatp2 in rat liver.  Gastroenterology . 1999;  117 688-695
• 64 Rausch-Derra L C, Hartley D P, Meier P J, Klaassen C D. Differential effects of microsomal enzyme-inducing chemicals on the hepatic expression of rat organic anion transporters, OATP1 and OATP2.  Hepatology . 2001;  33 1469-1478
• 65 Staudinger J L, Goodwin B, Jones S A. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.  Proc Natl Acad Sci USA . 2001;  98 3369-3374
• 66 Staudinger J, Liu Y, Madan A. Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane x receptor.  Drug Metab Dispos . 2001;  29 1467-1472
• 67 Williams M T, Leonard D, Simonet L. Effects of pregnenolone-16 α-carbonitrile on drug metabolizing enzymes in hypophysectomized female rats.  Life Sci . 1987;  41 1141-1148
• 68 Synold T W, Dussault I, Forman B M. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux.  Nat Med . 2001;  7 584-590
• 69 Gerbal-Chaloin S, Pascussi J M, Pichard-Garcia L. Induction of CYP2C genes in human hepatocytes in primary culture.  Drug Metab Dispos . 2001;  29 242-251
• 70 Madhu C, Klaassen C D. Protective effect of pregnenolone-16 α-carbonitrile on acetaminophen-induced hepatotoxicity in hamsters.  Toxicol Appl Pharmacol . 1991;  109 305-313
• 71 Liu L, Klaassen C D. Regulation of hepatic sulfotransferases by steroidal chemicals in rats.  Drug Metab Dispos . 1996;  24 854-858
• 72 Dunn R T, Gleason B A, Hartley D P, Klaassen C D. Postnatal ontogeny and hormonal regulation of sulfotransferase SULTIB1 in male and female rats.  J Pharmacol Exp Ther . 1999;  290 319-324
• 73 Runge-Morris M, Wu W, Kocarek T A. Regulation of rat hepatic hydroxysteroid sulfotransferase (SULT2-40/41) gene expression by glucocorticoids: evidence for a dual mechanism of transcriptional control.  Mol Pharmacol . 1999;  56 1198-1206
• 74 Hosokawa M, Hattori K, Satoh T. Differential responses of rat hepatic microsomal carboxylesterase isozymes to glucocorticoids and pregnenolone 16 α-carbonitrile.  Biochem Pharmacol . 1993;  45 2317-2322
• 75 Chiang J YL. Regulation of bile acid synthesis.  Front Biosci . 1998;  3 176-193
• 76 Iser J H, Dowling H, Mok H Y, Bell G D. Chenodeoxycholic acid treatment of gall stones. A follow-up report and analysis of factors influencing response to therapy.  N Engl J Med . 1975;  293 378-383
• 77 Schmucker D L, Ohta M, Kanai S. Hepatic injury induced by bile salts: correlation between biochemical and morphological events.  Hepatology . 1990;  12 1216-1221
• 78 Radominska A, Treat S, Little J. Bile acid metabolism and the pathophysiology of cholestasis.  Semin Liver Dis . 1993;  13 219-234
• 79 Radominska-Pyrek A, Zimniak P, Irshaid Y M. Glucuronidation of 6 α-hydroxy bile acids by human liver microsomes.  J Clin Invest . 1987;  80 234-241
• 80 Waxman D J, Attisano C, Guengerich F P, Lapenson D P. Human liver microsomal steroid metabolism: identification of the major microsomal steroid hormone 6 β-hydroxylase P-450.  Arch Biochem Biophys . 1988;  263 424-436
• 81 Summerfield J A, Billing B H, Shackleton C H. Identification of bile acids in the serum and urine in cholestasis.  Evidence for 6 α-hydroxylation of bile acids in man. Biochem J . 1976;  154 507-516
• 82 Salen G, Batta A K. Bile acid abnormalities in cholestatic liver diseases.  Gastroenterol Clin North Am . 1999;  28 173-193
• 83 Araya Z, Wikvall K. 6α-Hydroxylation of taurochenodeoxycholic acid and lithocholic acid by CYP3A4 in human liver microsomes.  Biochim Biophys Acta . 1999;  1438 47-54
• 84 Wietholtz H, Marschall H U, Sjovall J, Matern S. Stimulation of bile acid 6-α hydroxylation by rifampin.  J Hepatol . 1996;  24 713-718
• 85 Bachs L, Pares A, Elena M. Effects of long-term rifampicin administration in primary biliary cirrhosis.  Gastroenterology . 1992;  102 2077-2080
• 86 Xie W, Radominska-Pandya A, Shi Y. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids.  Proc Natl Acad Sci USA . 2001;  98 3375-3380
• 87 Chawla A, Saez E, Evans R M. ``Don't know much bile-ology''.  Cell . 2000;  103 1-4
• 88 Lu T T, Makishima M, Repa J J. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors.  Mol Cell . 2000;  6 507-515
• 89 Repa J J, Mangelsdorf D J. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis.  Annu Rev Cell Dev Biol . 2000;  16 459-481
• 90 Willson T M, Jones S A, Moore J T, Kliewer S A. Chemical genomics: functional analysis of orphan nuclear receptors in the regulation of bile acid metabolism.  Med Res Rev . 2001;  21 513-522