Activation of the constitutive androstane receptor decreases HDL in wild-type and human apoA-I transgenic mice

Abstract

The nuclear hormone receptor constitutive androstane receptor (CAR, NR1I3) regulates detoxification of xenobiotics and endogenous molecules, and has been shown to be involved in the metabolism of hepatic bile acids and cholesterol. The goal of this study was to address potential effects of CAR on the metabolism of HDL particles, key components in the reverse transport of cholesterol to the liver. Wild-type (WT) mice, transgenic mice expressing human apolipoprotein A-I (HuAITg), and CAR-deficient (CAR−/−) mice were treated with the specific CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). CAR activation decreased HDL cholesterol and plasma apolipoprotein A-I (apoA-I) levels in both WT and HuAITg mice, but not CAR−/− mice. Both mouse apoA-I and human apoA-I were decreased by more than 40% after TCPOBOP treatment, and kinetic studies revealed that the production rate of HDL is reduced in TCPOBOP-treated WT mice. In transient transfections, TCPOBOP-activated CAR decreased the activity of the human apoA-I promoter. Although loss of CAR function did not alter HDL levels in normal chow-fed mice, HDL cholesterol, apoA-I concentration, and apoA-I mRNA levels were increased in CAR−/− mice relative to WT mice when both were fed a high-fat diet. We conclude that CAR activation in mice induces a pronounced decrease in circulating levels of plasma HDL, at least in part through downregulation of apoA-I gene expression. The nuclear hormone receptor constitutive androstane receptor (CAR, NR1I3) regulates detoxification of xenobiotics and endogenous molecules, and has been shown to be involved in the metabolism of hepatic bile acids and cholesterol. The goal of this study was to address potential effects of CAR on the metabolism of HDL particles, key components in the reverse transport of cholesterol to the liver. Wild-type (WT) mice, transgenic mice expressing human apolipoprotein A-I (HuAITg), and CAR-deficient (CAR−/−) mice were treated with the specific CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). CAR activation decreased HDL cholesterol and plasma apolipoprotein A-I (apoA-I) levels in both WT and HuAITg mice, but not CAR−/− mice. Both mouse apoA-I and human apoA-I were decreased by more than 40% after TCPOBOP treatment, and kinetic studies revealed that the production rate of HDL is reduced in TCPOBOP-treated WT mice. In transient transfections, TCPOBOP-activated CAR decreased the activity of the human apoA-I promoter. Although loss of CAR function did not alter HDL levels in normal chow-fed mice, HDL cholesterol, apoA-I concentration, and apoA-I mRNA levels were increased in CAR−/− mice relative to WT mice when both were fed a high-fat diet. We conclude that CAR activation in mice induces a pronounced decrease in circulating levels of plasma HDL, at least in part through downregulation of apoA-I gene expression. Constitutive androstane receptor (CAR) belongs to the nuclear receptor family. It was first described as a xenobiotic sensor that responds to a broad range of ligands and regulates the expression of genes involved in both xenobiotic and endobiotic elimination pathways (1Willson T.M. Kliewer S.A. PXR, CAR and drug metabolism.Nat. Rev. Drug Discov. 2002; 1: 259-266Crossref PubMed Scopus (418) Google Scholar, 2Xie W. Yeuh M.F. Rodominska-Pandya A. Saini S.P.S. Negishi Y. Bottroff B.S. Cabrera G.Y. Tukey R.H. Evans R.M. Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor.Proc. Natl. Acad. Sci. USA. 2003; 100: 4150-4155Crossref PubMed Scopus (324) Google Scholar, 3Qatanani M. Moore D.D. CAR, the continuously advancing receptor, in drug metabolism and disease.Curr. Drug Metab. 2005; 6: 329-339Crossref PubMed Scopus (142) Google Scholar). Interestingly, several studies have highlighted the role of CAR in cholesterol and bile acid metabolism (4Guo G.L. Lambert G. Negishi M. Ward J.M. Brewer H.B. Kliewer S.A. Gonzalez F.J. Sinal C.J. Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity.J. Biol. Chem. 2003; 278: 45062-45071Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 5Uppal H. Toma D. Saini S.P. Ren S. Jones T.J. Xie W. Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice.Hepatology. 2005; 41: 168-176Crossref PubMed Scopus (98) Google Scholar, 6Stedman C.A. Liddle C. Coulter S.A. Sonoda J. Alvarez J.G. Moore D.D. Evans R.M. Downes M. Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury.Proc. Natl. Acad. Sci. USA. 2005; 102: 2063-2068Crossref PubMed Scopus (190) Google Scholar) and have suggested complementary roles for CAR, pregnane X receptor (PXR), and farnesoid X receptor (FXR) in preventing bile acid toxicity. CAR may also be able to modulate plasma cholesterol transport and lipoprotein metabolism, although recent studies on the effect of CAR activators on plasma lipoprotein levels in rodents and humans are inconclusive or ambiguous. For example, treatment of epileptic patients or rats with phenobarbital, a dual CAR/PXR activator in humans (7Lehmann D.D. McKee M.A. Watson T.M. Moore W.J.T. Kliewer S.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: 1016-1023Crossref PubMed Scopus (1389) Google Scholar), increases plasma cholesterol and lipoprotein levels (8Aynaci F.M. Orhan F. Orem A. Yildirmis S. Cedik Y. Effect of antiepileptic drugs on plasma lipoprotein (a) and other lipid levels in childhood.J. Child Neurol. 2001; 16: 367-369Crossref PubMed Scopus (40) Google Scholar, 9Romaschin A.D. Goldberg D.M. Effect of phenobarbital upon serum cholesterol lipoprotein fractions of three rodent species.Clin. Physiol. Biochem. 1987; 5: 77-84PubMed Google Scholar), and phenytoin, a nonspecific CAR activator (10Jackson J.P. Ferguson S.S. Moore R. Negishi M. Goldstein J.A. The constitutive active/androstane receptor regulates phenytoin induction of Cyp2C29.Mol. Pharmacol. 2004; 65: 1397-1404Crossref PubMed Scopus (43) Google Scholar, 11Wang H. Faucette S. Moore R. Sueyoshi T. Negishi M. Le Cluyse E. Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin.J. Biol. Chem. 2004; 279: 29295-29301Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 12Kobayashi K. Yamagami S. Higuchi T. Hosokawa M. Chiba K. Key structural features of ligands for activation of human pregnane X receptor.Drug Metab. Dispos. 2004; 32: 468-472Crossref PubMed Scopus (25) Google Scholar) that activates PXR and other plasma membrane receptors and channels, increases plasma HDL concentration in humans (13Miller M. Burgan R.G. Osterlund L. Segrest J.P. Garber D.W. A prospective, randomized trial of phenytoin in nonepileptic subjects with reduced HDL cholesterol.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 2151-2156Crossref PubMed Scopus (27) Google Scholar, 14Goerdt C. Keith M. Rubins H.B. Effects of phenytoin on plasma high-density lipoprotein cholesterol levels in men with low levels of high-density lipoprotein cholesterol.J. Clin. Pharmacol. 1995; 35: 767-775Crossref PubMed Scopus (18) Google Scholar). On the other hand, CAR-deficient (CAR−/−) mice exhibit higher HDL cholesterol levels than wild-type (WT) mice under cholestatic conditions following bile duct ligation, suggesting a negative effect of CAR on HDL metabolism, at least in that circumstance (6Stedman C.A. Liddle C. Coulter S.A. Sonoda J. Alvarez J.G. Moore D.D. Evans R.M. Downes M. Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury.Proc. Natl. Acad. Sci. USA. 2005; 102: 2063-2068Crossref PubMed Scopus (190) Google Scholar). To specifically assess how CAR affects lipoprotein metabolism, we treated WT mice, CAR−/− mice (15Wei P. Zhang J. Egan-Hafley M. Liang S. Moore D.D. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism.Nature. 2000; 407: 920-923Crossref PubMed Scopus (593) Google Scholar), and transgenic mice expressing human apolipoprotein A-I (apoA-I) (HuAITg mice) (16Rubin E.M. Ishida B.Y. Clift S.M. Krauss R.M. Expression of human apolipoprotein A-I in transgenic mice results in reduced plasma levels of murine apolipoprotein A-I and the appearance of two new high density lipoprotein size subclasses.Proc. Natl. Acad. Sci. USA. 1991; 88: 434-438Crossref PubMed Scopus (242) Google Scholar) with the specific CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) (17Tzameli I. Pissios P. Schuetz E.G. Moore D.D. The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR.Mol. Cell. Biol. 2000; 20: 2951-2958Crossref PubMed Scopus (364) Google Scholar). Such CAR activation causes a pronounced reduction in HDL cholesterol and apoA-I levels in WT and HuAITg mice, which is absent in CAR−/− mice. These results demonstrate that ligand-activated CAR influences HDL metabolism in WT and HuAITg mice. C57Bl6 WT mice, C57Bl6 mice, CAR−/− mice (15Wei P. Zhang J. Egan-Hafley M. Liang S. Moore D.D. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism.Nature. 2000; 407: 920-923Crossref PubMed Scopus (593) Google Scholar), and C57Bl6 transgenic mice expressing human apoA-I under the control of its natural flanking regions (HuAITg) (16Rubin E.M. Ishida B.Y. Clift S.M. Krauss R.M. Expression of human apolipoprotein A-I in transgenic mice results in reduced plasma levels of murine apolipoprotein A-I and the appearance of two new high density lipoprotein size subclasses.Proc. Natl. Acad. Sci. USA. 1991; 88: 434-438Crossref PubMed Scopus (242) Google Scholar) were used in the present study. TCPOBOP (Sigma-Aldrich; St. Louis, MO) was given at the dose of 3 mg/kg to the mice (8–10 weeks old; five mice per group) by one intraperitoneal injection with 100 μl of corn oil as a vehicle. Animals were euthanized 5 days after injection. Mice had free access to water and food, and they were placed on a standard chow diet (Standard AIN-93G rodent diet containing 58.6% carbohydrate, 18.1% protein, 7.2% and were by the of and and are in with the of For the high-fat diet the mice were on a high-fat diet for were with 100 μl of corn oil or TCPOBOP 5 days the of the On the of the mice were for The diet was diet protein, carbohydrate, and cholesterol. in were treated and mice the 5 Animals were euthanized with and were by in that were at for was and at were in and at mRNA and were on a cholesterol was by the 100 and cholesterol concentration was by the cholesterol cholesterol concentration was as the and free cholesterol. were by as described T. D. L. Le J. P. L. A. plasma lipoprotein by human in Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus (43) Google Scholar). concentration was acid HDL cholesterol and cholesterol were in and plasma were on a that was to a were at a rate with containing and cholesterol and were in fractions T. D. L. Le J. P. L. A. plasma lipoprotein by human in Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus (43) Google Scholar). and HDL were by as the and the were by the of were to on as by the were by and on a were by with that were in with the were by as the plasma with one in a in a were to a and was as by the were to and the of HDL were by with a The of HDL were by with to with the T. D. L. Le J. P. L. A. plasma lipoprotein by human in Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus (43) Google Scholar). HDL was with by the following containing and were by and were for at with WT HDL of mouse HDL was by at and density in a a Control and TCPOBOP-treated mice were euthanized and in the with HDL was the at and for of The were the of in plasma by the to a to the of The of with plasma Biol. PubMed Scopus Google Scholar). The production were by the by the plasma cholesterol and by the Human apoA-I levels were by an apoA-I concentration was by a plasma were to on as by the were by and on a The of apoA-I per was by with apoA-I which were in with the was were by the 5 of was and of the was were the following and human and mouse and was used as a gene its levels were not by TCPOBOP treatment and also the conditions were to of was with and were to mRNA levels were the regions and of the human gene were were in with were at a density of and was with For of CAR and 100 were after were with with serum containing TCPOBOP or were and with was used to the the with was used for with the specific CAR agonist TCPOBOP in plasma lipid in WT mice treatment, plasma levels of cholesterol and free cholesterol were decreased in plasma levels HDL cholesterol was by the TCPOBOP treatment in WT mice, and as as that plasma lipid were by an of the HDL A decrease in levels was also but did not to a to the decrease in plasma cholesterol In to plasma lipid plasma apoA-I concentration was reduced in TCPOBOP-treated WT mice in WT mice treated with TCPOBOP in WT mice the control In with the a reduction in a decrease in was by lipid in WT or CAR−/− mice or not the specific CAR agonist cholesterol cholesterol cholesterol cholesterol constitutive androstane the in a new of HDL C57Bl6 WT mice or not the CAR HDL size plasma were to on that were for as described in and HDL were by and the size was as with of lipoprotein and were by and were by were after and was by with the and of HDL and were as described in and are as of HDL cholesterol CAR, constitutive androstane the CAR is in an in the the lipoprotein of CAR−/− and WT mice were when were given a chow with for of the lipid and of plasma in CAR−/− mice and WT mice were The in plasma and apoA-I in WT mice were absent in CAR−/− mice. In was reduction in HDL cholesterol or apoA-I levels after treatment of CAR−/− mice with TCPOBOP and were CAR−/− mice or did not the CAR agonist The human apoA-I transgenic mouse (HuAITg) has been to be a for in the effect of HDL metabolism M. acid plasma levels of mouse and human apolipoprotein A-I a J. Biochem. 2000; PubMed Scopus Google Scholar, L. F. S. J. A. E. P. of human mouse apolipoprotein A-I by in human apolipoprotein A-I transgenic Clin. Invest. PubMed Scopus Google Scholar). (16Rubin E.M. Ishida B.Y. Clift S.M. Krauss R.M. Expression of human apolipoprotein A-I in transgenic mice results in reduced plasma levels of murine apolipoprotein A-I and the appearance of two new high density lipoprotein size subclasses.Proc. Natl. Acad. Sci. USA. 1991; 88: 434-438Crossref PubMed Scopus (242) Google Scholar), HuAITg mice increased apoA-I and cholesterol levels to an in the HDL and and (16Rubin E.M. Ishida B.Y. Clift S.M. Krauss R.M. Expression of human apolipoprotein A-I in transgenic mice results in reduced plasma levels of murine apolipoprotein A-I and the appearance of two new high density lipoprotein size subclasses.Proc. Natl. Acad. Sci. USA. 1991; 88: 434-438Crossref PubMed Scopus (242) Google Scholar, L. F. S. J. A. E. P. of human mouse apolipoprotein A-I by in human apolipoprotein A-I transgenic Clin. Invest. PubMed Scopus Google Scholar). and as with WT mice, TCPOBOP in the plasma lipoprotein of HuAITg mice, with in cholesterol, cholesterol, HDL cholesterol, and human apoA-I levels in in WT mice, the TCPOBOP treatment had effect on the plasma in HuAITg mice lipid concentration in HuAITg mice or not the specific CAR agonist TCPOBOP cholesterol cholesterol cholesterol cholesterol mice, transgenic mice expressing human apolipoprotein in a new HuAITg mice, transgenic mice expressing human apolipoprotein To the effect of CAR activation on HDL HDL was with of in plasma as but be in The of HDL to be increased in TCPOBOP-treated mice but the were not control and TCPOBOP-treated mice not the production rate was reduced in the TCPOBOP as with the control the expression of and CAR genes E.M. Krauss R.M. J.G. Clift S.M. of in transgenic mice by human apolipoprotein 1991; PubMed Scopus Google Scholar), was by TCPOBOP in the liver of WT and HuAITg mice, were in CAR−/− mice In TCPOBOP treatment of WT mice a reduction in the liver mRNA levels of apoA-I In HuAITg mice, the TCPOBOP treatment a reduction in the hepatic of mouse apoA-I and a reduction in the hepatic of human apoA-I in both were shown to specifically to CAR in apoA-I gene expression were in CAR−/− mice treated with To the that CAR at the three of the human were in with an expression for CAR, a of CAR function or with the as control were treated with or the CAR agonist CAR the activity of the apoA-I under and this effect was both by TCPOBOP and by the agonist In the effects were pronounced with CAR The was with the apoA-I but was for the results that the of the apoA-I a by Interestingly, this is and is more than to the mouse WT and CAR−/− mice were fed a high-fat diet for weeks to TCPOBOP with the chow-fed mice, CAR activation decreased cholesterol levels in the WT but not the CAR−/− mice. CAR−/− mice cholesterol, HDL cholesterol, and apoA-I levels relative to the WT mice were with apoA-I mRNA with higher levels in CAR−/− relative to WT mice lipid in WT and CAR−/− mice on high-fat diet or not the specific CAR agonist TCPOBOP TCPOBOP cholesterol wild-type high-fat wild-type high-fat wild-type high-fat TCPOBOP cholesterol wild-type high-fat wild-type high-fat wild-type high-fat TCPOBOP cholesterol wild-type high-fat TCPOBOP cholesterol wild-type high-fat wild-type high-fat wild-type high-fat TCPOBOP wild-type high-fat wild-type high-fat TCPOBOP the wild-type high-fat wild-type high-fat TCPOBOP in a new and mRNA levels in the liver of C57Bl6 WT mice and CAR−/− mice fed a high-fat diet and treated or not treated with the CAR agonist were the and apoA-I and mRNA levels were by as described in and were with as and mRNA levels in mice treated with corn oil were at are with WT mice the CAR, a of the nuclear receptor was described as a xenobiotic sensor (1Willson T.M. Kliewer S.A. PXR, CAR and drug metabolism.Nat. Rev. Drug Discov. 2002; 1: 259-266Crossref PubMed Scopus (418) Google Scholar, 2Xie W. Yeuh M.F. Rodominska-Pandya A. Saini S.P.S. Negishi Y. Bottroff B.S. Cabrera G.Y. Tukey R.H. Evans R.M. Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor.Proc. Natl. Acad. Sci. USA. 2003; 100: 4150-4155Crossref PubMed Scopus (324) Google Scholar, 3Qatanani M. Moore D.D. CAR, the continuously advancing receptor, in drug metabolism and disease.Curr. Drug Metab. 2005; 6: 329-339Crossref PubMed Scopus (142) Google Scholar). its key role in elimination pathways of endogenous has been In a of studies have the CAR and hepatic acid metabolism (4Guo G.L. Lambert G. Negishi M. Ward J.M. Brewer H.B. Kliewer S.A. Gonzalez F.J. Sinal C.J. Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity.J. Biol. Chem. 2003; 278: 45062-45071Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 5Uppal H. Toma D. Saini S.P. Ren S. Jones T.J. Xie W. Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice.Hepatology. 2005; 41: 168-176Crossref PubMed Scopus (98) Google Scholar, 6Stedman C.A. Liddle C. Coulter S.A. Sonoda J. Alvarez J.G. Moore D.D. Evans R.M. Downes M. Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury.Proc. Natl. Acad. Sci. USA. 2005; 102: 2063-2068Crossref PubMed Scopus (190) Google Scholar, M. Schuetz E.G. M. D. K. G. M. S. Evans R.M. hepatic and as revealed by the constitutive androstane receptor and Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). CAR is able to the liver against bile acid by expression of genes involved in the of bile acids at the of and toxic E. Liddle C. of the human CYP3A4 gene by the constitutive androstane Pharmacol. 2002; PubMed Scopus Google Scholar, J. W. M. Evans R.M. Moore D.D. The constitutive androstane receptor and pregnane X receptor function to bile Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar), the of bile acids M. Schuetz E.G. M. D. K. G. M. S. Evans R.M. hepatic and as revealed by the constitutive androstane receptor and Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar, S.P. Sonoda J. L. Toma D. H. Y. Ren S. Moore D.D. Evans R.M. Xie W. A constitutive androstane and of bile acid Pharmacol. 2004; 65: PubMed Scopus Google Scholar), and the of bile acids M. Schuetz E.G. M. D. K. G. M. S. Evans R.M. hepatic and as revealed by the constitutive androstane receptor and Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). The present study that activation of CAR by TCPOBOP plasma HDL levels in WT mice but not in CAR−/− mice. CAR is under conditions as CAR did not in plasma lipoprotein of chow-fed a high-fat diet for CAR−/− mice a in cholesterol levels relative to WT mice. is with an in plasma HDL in CAR−/− mice placed under cholestatic conditions (6Stedman C.A. Liddle C. Coulter S.A. Sonoda J. Alvarez J.G. Moore D.D. Evans R.M. Downes M. Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury.Proc. Natl. Acad. Sci. USA. 2005; 102: 2063-2068Crossref PubMed Scopus (190) Google Scholar). These the of a negative effect of activated CAR on HDL levels in mice. the liver X receptors effect on HDL in fed standard a function of in HDL metabolism was in treated with cholesterol or other specific W. J.M. and bile acid metabolism are in mice the nuclear receptor 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, S. G. P. D. M. I. S. J.A. cholesterol metabolism and to cholesterol in Clin. Invest. 2001; PubMed Scopus Google Scholar). To the that for the reduced levels in TCPOBOP-treated kinetic of HDL with was The production rate of HDL was in the TCPOBOP-treated in with reduced apoA-I mRNA that an of the of HDL at least in part to the is a structural of HDL (16Rubin E.M. Ishida B.Y. Clift S.M. Krauss R.M. Expression of human apolipoprotein A-I in transgenic mice results in reduced plasma levels of murine apolipoprotein A-I and the appearance of two new high density lipoprotein size subclasses.Proc. Natl. Acad. Sci. USA. 1991; 88: 434-438Crossref PubMed Scopus (242) Google Scholar), and its expression is a of circulating HDL Interestingly, in HuAITg mice, both mouse and human apoA-I mRNA levels were decreased by TCPOBOP treatment, and in plasma levels of human apoA-I were in the of both mouse and human apoA-I gene expression with in studies of the of the apoA-I In receptor are to the human apoA-I they mouse apoA-I gene expression L. F. S. J. A. E. P. of human mouse apolipoprotein A-I by in human apolipoprotein A-I transgenic Clin. Invest. PubMed Scopus Google Scholar). The present study that this of the mouse not to the of apoA-I expression by CAR that to effects on rodent and human the effect of CAR on plasma lipoprotein metabolism in humans Human studies were with phenobarbital or phenytoin, are nonspecific CAR in plasma HDL cholesterol and apoA-I levels (8Aynaci F.M. Orhan F. Orem A. Yildirmis S. Cedik Y. Effect of antiepileptic drugs on plasma lipoprotein (a) and other lipid levels in childhood.J. Child Neurol. 2001; 16: 367-369Crossref PubMed Scopus (40) Google Scholar, J.P. Ferguson S.S. Moore R. Negishi M. Goldstein J.A. The constitutive active/androstane receptor regulates phenytoin induction of Cyp2C29.Mol. Pharmacol. 2004; 65: 1397-1404Crossref PubMed Scopus (43) Google Scholar, 11Wang H. Faucette S. Moore R. Sueyoshi T. Negishi M. Le Cluyse E. 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In the present study that CAR activation plasma HDL metabolism in WT and HuAITg mice. It is that the reverse cholesterol transport to the of CAR to normal liver function downregulation of bile acid and toxicity.