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Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan (S.D.S., N.A.M.-H., M.A., M.D.G., M.R.M., T.A.K.) and Department of Chemistry, Dartmouth College, Hanover, New Hampshire (T.A.S.)
(Received July 22, 2003; accepted September 11, 2003)
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Abstract |
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/ß- or pregnane X receptor (PXR)-null mice. CYP3A mRNA levels were increased after treatment with 24(S),25-epoxycholesterol in both wild-type and LXR-null mouse hepatocytes. In contrast, neither 24(S),25-epoxycholesterol nor either of two additional potent LXR ligands, 22(R)-hydroxycholesterol and N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl-]phenyl]-benzenesulfonamide (T0901317), altered CYP3A mRNA levels in hepatocytes prepared from PXR-null mice, although these agents induced CYP3A mRNA content in wild-type cultures. As evidence that the LXR ligands also activated PXR in rat hepatocytes, cotransfection of primary cultures with a dominant negative PXR abolished reporter gene induction after treatment with any of the test agents. These results indicate that selected LXR ligands are capable of activating PXR, probably as a defensive measure to prevent the accumulation of these potentially toxic endogenous molecules.
; Zhang et al., 2001). In contrast, appreciable amounts of 24(S),25-epoxycholesterol are produced within the cell (Zhang et al., 2001) through a pathway parallel to that for cholesterol biosynthesis, which begins with the diversion of squalene 2,3-oxide to squalene 2,3:22,23-dioxide (Nelson et al., 1981). Oxysterols first achieved notice as molecules capable of inhibiting cholesterol biosynthesis (Kandutsch et al., 1978), an effect that was subsequently attributed to the suppressed expression of genes regulated by the sterol regulatory element binding protein class of transcription factors (Brown and Goldstein, 1997). More recently, certain oxysterols, including those mentioned above, have been shown to be potent and effective activators of the LXR1 class of nuclear receptors (Janowski et al., 1996; Forman et al., 1997; Lehmann et al., 1997). The binding affinities of 24(S),25-epoxycholesterol and 22(R)-hydroxycholesterol for LXR have been reported to be 200 and 380 nM, respectively, although their EC50 values for activation of LXR in cotransfection assays have been measured as 4 and 5 µM, respectively (Janowski et al., 1999). Oxysterol-activated LXR activity is responsible for up-regulating the expression of several genes involved in maintaining hepatic and extrahepatic cholesterol homeostasis. In the liver this includes CYP7A1, the rate-limiting step in bile acid biosynthesis (Peet et al., 1998).
In addition to those nuclear receptors that function primarily as regulators of cellular lipid homeostasis, such as the LXR and the bile acid receptor farnesoid X receptor (Makishima et al., 1999; Parks et al., 1999; Wang et al., 1999), a class of receptors exists that function as "xenobiotic sensors" (Xie and Evans, 2001). Xenobiotic-mediated activation of one of these receptors induces the expression of a battery of phase I, phase II, and transporter enzymes as a concerted defense aimed at eliminating the foreign agent from the cell. Thus, PXR has been convincingly shown to be the primary mediator of steroid-, drug-, and environmental chemical-inducible CYP3A gene transcription (Kliewer et al., 1998; Lehmann et al., 1998), whereas CAR has likewise been shown to mediate the effects of phenobarbital and phenobarbital-like chemicals on CYP2B expression (Wei et al., 2000; Ueda et al., 2002). In comparison with other nuclear receptors, the ligand binding domains of PXR and CAR are poorly conserved across species, reflecting the well documented interspecies differences in P450 induction responsiveness to various chemicals (Xie and Evans, 2001). The ability of PXR to function as a broad sensor of xenobiotics is supported by crystallographic analyses indicating that this receptor has a very large ligand binding cavity (Watkins et al., 2001, 2003).
Growing evidence indicates that the xenobiotic-sensing receptors also play important roles in protecting the cell against the accumulation of toxic endogenous intermediates. For example, the cholestatic bile acid lithocholic acid is metabolized via CYP3A-catalyzed 6- and 6ß-hydroxylations (Xie et al., 2001) and is an effective activator of PXR (Staudinger et al., 2001; Xie et al., 2001). Certain bile acid precursors, such as 5ß-cholestane-3,7,12-triol, which accumulate in the absence of functional CYP27, activate the PXR and induce CYP3A in mouse, but not human, hepatocytes (Dussault et al., 2003; Goodwin et al., 2003). CYP3A-catalyzed metabolism of 5ß-cholestane-3,7,12-triol initiates an alternative pathway of sterol side chain shortening, permitting the formation of cholic acid (Honda et al., 2001; Goodwin et al., 2003). This species difference in CYP3A induction and metabolism explains why humans with the genetic disease cerebrotendinous xanthomatosis produce reduced levels of normal bile acids, accumulate sterols in various tissues, and exhibit a host of severe pathologies, whereas mice that have been genetically engineered to lack CYP27 do not (Dussault et al., 2003; Goodwin et al., 2003).
We have been investigating the effects of drugs that interfere with cholesterol biosynthesis on the expression of xenobiotic-metabolizing P450s (Kocarek and Mercer-Haines, 2002; Kocarek et al., 2002a). During the course of these studies, we found that treatment of primary cultures of rat hepatocytes with the oxysterol, 25-hydroxycholesterol, produced increased CYP3A expression. This observation prompted us to determine whether other molecules of the oxysterol class were capable of causing CYP3A induction in hepatocyte cultures, and if true, to determine which receptor, the oxysterol receptor LXR or the xenosensor receptor PXR, was responsible for mediating the effect.
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Materials and Methods |
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). The sterol was homogenous by thin-layer chromatography, and no impurities were detectable by 1H or 13C NMR. Ciprofibrate and T0901317 (purity 
98%) were gifts from Sterling Winthrop Pharmaceuticals, Inc. (Rensselaer, NY) and Tularik, Inc. (San Francisco, CA), respectively. Dexamethasone, 22(R)-hydroxycholesterol (purity 98%), 25-hydroxycholesterol, ß-naphthoflavone, phenobarbital, and PCN were purchased from Sigma-Aldrich (St. Louis, MO). Matrigel was purchased from BD Biosciences Discovery Labware (Bedford, MA). Vitrogen was purchased from Cohesion Technologies, Inc. (Palo Alto, CA). Recombinant human insulin (Novolin R) was purchased from Novo Nordisk Pharmaceuticals, Inc. (Princeton, NJ). Culture medium and Lipofectin reagent were purchased from Invitrogen (Carlsbad, CA). Nylon hybridization filters (Gene Screen Plus) were purchased from Perkin Elmer Life and Analytical Sciences (Boston, MA). Nitrocellulose membranes were purchased from Bio-Rad (Hercules, CA). Enhanced chemiluminescence Western blot reagents were purchased from Amersham Biosciences Inc. (Piscataway, NJ). Polyclonal antibodies to CYP1A1 (specific for CYP1A1) and CYP2B1 (cross-reactive with CYP2B2 and possibly other rat CYP2B proteins) were purchased from XenoTech LLC (Lenexa, KS). CYP4A1 antibody (cross-reactive with CYP4A2 and CYP4A3) was purchased from BD Gentest (Woburn, MA). A polyclonal antibody to CYP3A1 (expected to be cross-reactive with CYP3A2 and CYP3A23) was a gift from Dr. Janis Hulla (United States Army Corps of Engineers, Sacramento, CA).
Primary Culture of Rat and Mouse Hepatocytes. Hepatocytes were isolated from adult male Sprague-Dawley rats (250–350 g; Harlan, Indianapolis, IN), from adult male LXR/ß-null mice or their C57BL/6NxSv/129 wild-type counterparts (provided by Dr. David Mangelsdorf, University of Texas Southwestern Medical Center, Dallas, TX) (Peet et al., 1998) or from adult male PXR-null mice or their wild-type counterparts (20–30 g; Taconic Farms, Germantown, NY) (Staudinger et al., 2001; Wu et al., 2001). After isolation, 3 million viable hepatocytes were plated onto 60-mm Matrigel-coated dishes (for Northern blot experiments) or 300,000 viable hepatocytes were plated onto Vitrogen-coated wells in 12-well plates (for transient transfection experiments) and maintained in Williams' E medium supplemented with 0.25 U/ml insulin, 10–7 M triamcinolone acetonide, 100 U/ml penicillin, and 100 µg/ml streptomycin. Culture medium was renewed every 24 h. Drugs were added to the culture medium as concentrated stock solutions in water (phenobarbital), DMSO (ciprofibrate, dexamethasone, ß-naphthoflavone, PCN, and T0901317) or ethanol [22(R)-hydroxycholesterol, 25-hydroxycholesterol, and 24(S),25-epoxycholesterol]. When used, the final concentration of organic solvent in the culture medium was 0.1%.
Northern Blot Analysis. Beginning 48 h after plating, hepatocyte cultures were treated with drugs or sterols (three dishes per treatment group for rat hepatocytes; one to two dishes per treatment group for mouse hepatocytes), as described in the individual figure legends. After treatment, the dishes representing each treatment group were pooled for preparation of total RNA, using the Totally RNA kit (Ambion, Inc., Austin, TX). Ten-microgram samples of the pooled RNAs were resolved on denaturing agarose gels and analyzed by Northern blot hybridization using cDNA probes to CYP1A1 (containing 756 nt of the rat CYP1A1 3'-untranslated region; hybridizes specifically with CYP1A1 mRNA), CYP2B1 (full-length CYP2B1 cDNA; cross-reactive with multiple CYP2B mRNAs), CYP3A23 (containing the 3'-terminal 456 nt of the coding sequence and the 3'-untranslated region of CYP3A23; cross-reactive with multiple CYP3A mRNAs), and CYP4A1 (full-length CYP4A1 cDNA; cross-reactive with multiple CYP4A mRNAs), as previously described (Kocarek and Reddy, 1996). After autoradiography, radiolabeled probes were removed from the filters, and blots were rehybridized with 7 S cDNA to control for RNA loading and transfer.
Western Blot Analysis. Microsomes were isolated from five pooled dishes of primary cultured rat hepatocytes per treatment group. Western blot analysis was performed as previously described (Kocarek et al., 1998).
Transient Transfection of Primary Cultured Rat Hepatocytes. Primary cultures of rat hepatocytes were transiently transfected with reporter and expression constructs, as previously described (Kocarek and Mercer-Haines, 2002). The luciferase reporter plasmid contained three concatamerized copies of the CYP3A23-DR3 motif ligated upstream of a minimal herpes simplex virus thymidine kinase promoter (Kocarek and Mercer-Haines, 2002). Plasmids expressing wild-type or dominant negative PXR or PPAR have been recently described (Kocarek et al., 2002b). The dominant negative PXR and PPAR cDNAs lack the 3'-terminal nt encoding the activator function-2 subdomains, resulting in the expression of receptors presumed to be capable of undergoing normal heterodimerization and DNA binding but incapable of producing transcriptional activation. Transient transfection data were analyzed by one-way analysis of variance followed by the Newman-Keuls multiple comparison test (GraphPad Software, Inc., San Diego, CA).
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Results |
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and LXRß (Janowski et al., 1999; Spencer et al., 2001), we examined the effects of 25-hydroxycholesterol and 24(S),25-epoxycholesterol treatments on P450 mRNA levels in primary cultured rat hepatocytes (Fig. 1). Although neither of the oxysterols increased the amount of CYP1A1, CYP2B,2 or CYP4A mRNA, each sterol did produce a concentration-dependent suppression of CYP2B mRNA levels relative to that observed in ethanol-treated control cultures. In contrast, treatment with either of the oxysterols produced a concentration-dependent increase in the amount of CYP3A mRNA. Although the magnitude of the response elicited by 25-hydroxycholesterol treatment was small, the amount of CYP3A mRNA that was measured after treatment with 3 x 10–5 M 24(S),25-epoxycholesterol reached almost 50% of that seen after treatment with the prototypical CYP3A inducer, dexamethasone. Evaluation of sterol-mediated effects on P450 immunoreactive protein levels confirmed that 24(S),25-epoxycholesterol was a selective and effective inducer of CYP3A in primary cultured rat hepatocytes.
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To identify the pathway responsible for mediating the effects of sterol treatments on CYP3A expression, we chose to take advantage of available mouse models engineered to be null for individual or combinations of nuclear receptors. Because a prototypical ligand for LXR was found to be an efficacious inducer of CYP3A, we first tested the possibility that this response was mediated through an LXR, using hepatocyte cultures prepared from male mice null for both LXR and -ß (Fig. 2). CYP3A mRNA levels were increased after treatment with 24(S),25-epoxycholesterol in both wild-type and LXR-null mouse hepatocytes, indicating that sterol-inducible CYP3A expression does not require the presence of an LXR. Therefore, since PXR is the confirmed mediator of CYP3A induction by a variety of xenobiotic and endogenous agents, we performed the next series of studies in primary hepatocytes prepared from male PXR-null mice (Fig. 3). Along with 24(S),25-epoxycholesterol, we tested two additional potent LXR ligands, the oxysterol 22(R)-hydroxycholesterol and the synthetic LXR agonist T0901317. Treatment of wild-type hepatocyte cultures with either 3 x 10–5 M 24(S),25-epoxycholesterol or 10–5 M T0901317 markedly increased the amount of CYP3A mRNA. In contrast, 22(R)-hydroxycholesterol treatment evoked only a slight elevation in CYP3A mRNA content at a concentration of 5 x 10–5 M, which was the most effective concentration tested in a preliminary concentration-response experiment conducted in wild-type mouse hepatocyte cultures, although higher concentrations were not tested (data not shown). Likewise, 22(R)-hydroxycholesterol proved to be a weak inducer of CYP3A mRNA when incubated with primary cultured rat hepatocytes (data not shown). CYP3A induction did not occur in the PXR-null mouse hepatocyte cultures, indicating that each of the LXR ligands induced CYP3A as a consequence of PXR activation. As a control, phenobarbital-inducible CYP2B mRNA expression, mediated through CAR, was intact in the PXR-null hepatocyte cultures (data not shown).
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To establish whether the various LXR ligands were also capable of activating PXR in rat, the effects of transiently transfecting primary cultured rat hepatocytes with a plasmid encoding a dominant negative PXR were examined on the inducible expression of a cotransfected PXR-responsive luciferase reporter plasmid, containing three copies of the CYP3A23 DR3 nuclear receptor motif (Fig. 4). Each of the LXR ligands evoked a significant increase in PXR-regulated reporter gene expression. By comparison with its small effect on endogenous CYP3A mRNA content, 3 x 10–5 M 22(R)-hydroxycholesterol treatment increased expression from the transfected reporter plasmid to a greater extent than did 24(S),25-epoxycholesterol. Cotransfection with plasmid encoding wild-type PXR had no significant effect on LXR ligand-inducible reporter gene expression, although a partial but significant suppression of PCN-mediated reporter induction was observed, which was not reproduced in a replicate experiment (data not shown). In contrast, transfection with dominant negative PXR abolished the luciferase induction produced by PCN and each of the LXR ligands. As a control, transfection with plasmid expressing either wild-type or dominant negative PPAR had no effect on the ability of any of the agents to induce the expression of the PXR-responsive reporter.
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Discussion |
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) reported that the feeding of a cholesterol-rich diet to rats resulted in 2-fold increases in hepatic microsomal p-nitroanisole O-demethylase and ethoxycoumarin deethylase activities as compared with the activities measured in rats receiving a cholesterol-free diet. More recently, Plewka and Kaminski (1996) found that feeding a high cholesterol diet to rats resulted in suppression of hepatic basal and phenobarbital-inducible P450 content and aniline hydroxylase and 4-aminopyrine N-demethylase activities. Reduced hepatic levels of several P450-dependent activities were also measured in spontaneously hyperlipidemic rats that had 
3- to 4-fold higher serum cholesterol levels than did their wild-type counterparts (Watanabe et al., 1996). After the discovery and characterization of various "orphan" nuclear receptors, the mechanisms underlying these observations are becoming clarified. Thus, it is now known that certain bile acids and intermediates in bile acid biosynthesis are PXR activators and CYP3A inducers (Staudinger et al., 2001; Xie et al., 2001; Dussault et al., 2003; Goodwin et al., 2003). In this study, we have found that two oxysterols and one drug previously characterized as potent and effective activators of LXR are also capable of activating a PXR-mediated response in primary cultured rat and mouse hepatocytes. The endogenously synthesized oxysterol, and likely important regulator of LXR activity in vivo, 24(S),25-epoxycholesterol, was a particularly potent and effective CYP3A inducer, causing marked CYP3A accumulation at a concentration of 10 µM and maximal induction at 30–50 µM. By contrast, the EC50 of this agent for activating LXR in a cotransfection assay was 4 µM (Janowski et al., 1999). These findings provide further validation that PXR is the major mediator of CYP3A induction, whether the inducer is of xenobiotic or endogenous origin and whether or not the inducer is a known activator of another class of receptor. These results also provide support for the concept that there is substantial overlap between the mechanisms governing the metabolism of endogenous lipophilic agents and their xenobiotic counterparts. Treatment of primary cultured rat or mouse hepatocytes with these particular LXR ligands activated the PXR-mediated response at concentrations only marginally greater than those known to activate LXR. This is suggestive of a response continuum whereby physiological concentrations of oxysterols regulate the expression of key enzymes that are normally involved in maintaining sterol homeostasis. At only slightly higher concentrations, these same oxysterols are regarded as hazardous to the cell, thereby triggering the expression of enzymes that facilitate the elimination of potentially toxic molecules.
Current conventions suggest that the ability of a drug to function as an inducer of CYP3A transcription may be predicted by assessing the agent's ability to bind directly to PXR. However, based on the accumulating data indicating that some endogenous metabolites are also capable of activating PXR, it is important to consider the possibility that a drug may cause CYP3A induction indirectly, by interfering with a cellular process that controls the cellular content of such a bioactive endogenous molecule. In this regard, we have recently reported that squalestatin 1 potently induces CYP2B expression in primary cultured rat hepatocytes as a consequence of squalene synthase inhibition and resultant accumulation of an endogenous isoprenoid (Kocarek and Mercer-Haines, 2002). More recently, we have found that inhibitors of 2,3-oxidosqualene/lanosterol cyclase cause CYP3A induction in primary cultured rat and mouse hepatocytes and that these effects are completely abolished if the hepatocytes are cotreated with pravastatin, thus shutting off flux through the cholesterol biosynthetic pathway (S. D. Shenoy, T. Spencer, N. Mercer-Haines, M. Alipour, W. Wurster, M. Runge-Morris, and T. Kocarek, manuscript submitted for publication). Since the inhibition of 2,3-oxidosqualene/lanosterol cyclase has been reported to cause the accumulation of squalene 2,3-oxide, squalene 2,3:22,23-dioxide, and 24(S),25-epoxycholesterol levels (Mark et al., 1996; Morand et al., 1997), this raises the possibility that one of these endogenous metabolites may be responsible for mediating the observed effects of 2,3-oxidosqualene/lanosterol cyclase inhibitors on CYP3A expression.
We have not yet determined whether or not oxysterols themselves are direct PXR ligands, nor whether further biotransformation is necessary to generate the ultimate bioactive species. To obtain a more complete understanding of the biological basis for the observed effects, future studies will need to determine whether the oxysterol CYP3A inducers are substrates for CYP3A-catalyzed metabolism or for metabolism by some other PXR-regulated enzyme, such as hydroxysteroid sulfotransferase (Duanmu et al., 2002; Sonoda et al., 2002). Finally, in light of the previously documented differences in the abilities of the bile acid precursor sterols to activate mouse and human PXR (Dussault et al., 2003; Goodwin et al., 2003), it will be essential to assess the human significance of our findings by determining the degree to which the abilities of LXR ligands to induce CYP3A expression are conserved in the human hepatocyte.
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Acknowledgments |
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/ß-null mice and Drs. Bryan Goodwin and Steven Kliewer for facilitating acquisition of the PXR-null mice that were used in these studies. |
Footnotes |
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1 Abbreviations used are: LXR, liver X receptor; CAR, constitutive androstane receptor; PXR, pregnane X receptor; P450, cytochrome P450; T0901317, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide; PCN, pregnenolone 16-carbonitrile; DMSO, dimethyl sulfoxide; nt, nucleotide; PPAR, peroxisome proliferator-activated receptor . 
2 Because the P450 cDNA and antibody probes detect multiple related mRNA or protein species, the specific bands detected on the Northern or Western blot with the CYP2B1, CYP3A1/23, and CYP4A1 probes are referred to as CYP2B, CYP3A, and CYP4A, respectively.
Address correspondence to: Dr. Thomas A. Kocarek, Institute of Environmental Health Sciences, 2727 Second Avenue, Room 4000, Detroit, MI 48201. E-mail: t.kocarek{at}wayne.edu
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