Rexinoids Modulate Steroid and Xenobiotic Receptor Activity by Increasing Its Protein Turnover in a Calpain-dependent Manner

The steroid and xenobiotic receptor SXR (human pregnane X receptor) is a nuclear receptor that plays a key role in the body's detoxification response by regulating genes involved in drug metabolism and transport. SXR ligands include a wide range of compounds, which induce transcription of SXR target genes via activation of a heterodimeric transcription factor consisting of SXR and the related nuclear receptor retinoid X receptor (RXR). We investigated the effect of RXR-selective ligands, rexinoids, on SXR/RXR activity. In agreement with previous reports, we found that rexinoids are weak activators of SXR, but we also found that they can antagonize SXR activation by the potent SXR agonist rifampicin. This antagonism included suppression of rifampicin-induced expression of SXR target genes, as well as reduced binding of SXR/RXR to SXR response elements both in vivo and in vitro. Interestingly, two rexinoids, bexarotene (LGD1069/Targretin®) and LG100268, caused a rapid and sustained decrease in the protein levels of both SXR and RXR. The decrease in SXR level was due to an enhanced rate of protein degradation and was dependent on calpain activity, as opposed to rexinoid-induced RXR degradation, which is mediated via the proteasome. Thus, we have demonstrated a novel, rexinoid-modulated mechanism regulating SXR protein stability, which may explain why rexinoids are only weak activators of SXR/RXR-mediated transcription, despite reports that they bind to SXR with high affinity. We suggest that the ability of rexinoids to induce degradation of both SXR and RXR, in combination with competition for binding to SXR, can also explain why rexinoids antagonize the activation of SXR by drugs like rifampicin. The steroid and xenobiotic receptor SXR (human pregnane X receptor) is a nuclear receptor that plays a key role in the body's detoxification response by regulating genes involved in drug metabolism and transport. SXR ligands include a wide range of compounds, which induce transcription of SXR target genes via activation of a heterodimeric transcription factor consisting of SXR and the related nuclear receptor retinoid X receptor (RXR). We investigated the effect of RXR-selective ligands, rexinoids, on SXR/RXR activity. In agreement with previous reports, we found that rexinoids are weak activators of SXR, but we also found that they can antagonize SXR activation by the potent SXR agonist rifampicin. This antagonism included suppression of rifampicin-induced expression of SXR target genes, as well as reduced binding of SXR/RXR to SXR response elements both in vivo and in vitro. Interestingly, two rexinoids, bexarotene (LGD1069/Targretin®) and LG100268, caused a rapid and sustained decrease in the protein levels of both SXR and RXR. The decrease in SXR level was due to an enhanced rate of protein degradation and was dependent on calpain activity, as opposed to rexinoid-induced RXR degradation, which is mediated via the proteasome. Thus, we have demonstrated a novel, rexinoid-modulated mechanism regulating SXR protein stability, which may explain why rexinoids are only weak activators of SXR/RXR-mediated transcription, despite reports that they bind to SXR with high affinity. We suggest that the ability of rexinoids to induce degradation of both SXR and RXR, in combination with competition for binding to SXR, can also explain why rexinoids antagonize the activation of SXR by drugs like rifampicin. The steroid and xenobiotic receptor SXR 2The abbreviations used are: SXRsteroid and xenobiotic receptorSXRESXR response elementPXRpregnane X receptorRXRretinoid X receptorRARretinoic acid receptorLXRliver X receptorDMSOdimethyl sulfoxideEMSAelectrophoretic mobility shift assay. (human PXR) plays a key role in the body's detoxification response as a regulator of several genes involved in drug metabolism and transport (1Geick A. Eichelbaum M. Burk O. J. Biol. Chem. 2001; 276: 14581-14587Abstract Full Text Full Text PDF PubMed Scopus (769) Google Scholar, 2Synold T.W. Dussault I. Forman B.M. Nat. Med. 2001; 7: 584-590Crossref PubMed Scopus (760) Google Scholar, 3Kast H.R. Goodwin B. Tarr P.T. Jones S.A. Anisfeld A.M. Stoltz C.M. Tontonoz P. Kliewer S. Willson T.M. Edwards P.A. J. Biol. Chem. 2002; 277: 2908-2915Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar, 4Teng S. Jekerle V. Piquette-Miller M. Drug Metab. Dispos. 2003; 31: 1296-1299Crossref PubMed Scopus (120) Google Scholar, 5Goodwin B. Hodgson E. Liddle C. Mol. Pharmacol. 1999; 56: 1329-1339Crossref PubMed Scopus (592) Google Scholar). SXR ligands comprise a structurally diverse group of compounds, including natural and synthetic steroids and many xenobiotics, such as the antibiotic rifampicin, the insulin-sensitizing drug troglitazone, the cholesterol-lowering drug SR12813, and the anti-cancer drugs paclitaxel, cisplatin, and tamoxifen (2Synold T.W. Dussault I. Forman B.M. Nat. Med. 2001; 7: 584-590Crossref PubMed Scopus (760) Google Scholar, 6Lehmann J.M. McKee D.D. Watson M.A. Willson T.M. Moore J.T. Kliewer S.A. J. Clin. Investig. 1998; 102: 1016-1023Crossref PubMed Scopus (1385) Google Scholar, 7Blumberg B. Sabbagh Jr., W. Juguilon H. Bolado Jr., J. van Meter C.M. Ong E.S. Evans R.M. Genes Dev. 1998; 12: 3195-3205Crossref PubMed Scopus (819) Google Scholar, 8Jones S.A. Moore L.B. Shenk J.L. Wisely G.B. Hamilton G.A. McKee D.D. Tomkinson N.C. LeCluyse E.L. Lambert M.H. Willson T.M. Kliewer S.A. Moore J.T. Mol. Endocrinol. 2000; 14: 27-39Crossref PubMed Scopus (543) Google Scholar, 9Masuyama H. Suwaki N. Tateishi Y. Nakatsukasa H. Segawa T. Hiramatsu Y. Mol. Endocrinol. 2005; 19: 1170-1180Crossref PubMed Scopus (107) Google Scholar, 10Bertilsson G. Heidrich J. Svensson K. Asman M. Jendeberg L. Sydow-Backman M. Ohlsson R. Postlind H. Blomquist P. Berkenstam A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 12208-12213Crossref PubMed Scopus (795) Google Scholar, 11Nagaoka R. Iwasaki T. Rokutanda N. Takeshita A. Koibuchi Y. Horiguchi J. Shimokawa N. Iino Y. Morishita Y. Koibuchi N. Endocrine. 2006; 30: 261-268Crossref PubMed Scopus (26) Google Scholar). Because activation of SXR by these drugs induces transcription of genes like CYP3A4 and MDR1, SXR is a central regulator of drug/drug interactions and may also play a role in the development of resistance to chemotherapy in tumor cells (2Synold T.W. Dussault I. Forman B.M. Nat. Med. 2001; 7: 584-590Crossref PubMed Scopus (760) Google Scholar). SXR is a member of the nuclear receptor superfamily (subfamily 1, group I, member 2) and as such is a ligand-inducible transcription factor for which transcriptional activity requires heterodimerization with the retinoid X receptor, RXR (7Blumberg B. Sabbagh Jr., W. Juguilon H. Bolado Jr., J. van Meter C.M. Ong E.S. Evans R.M. Genes Dev. 1998; 12: 3195-3205Crossref PubMed Scopus (819) Google Scholar). The SXR/RXR heterodimer binds to a variety of response elements in target gene promoters, including direct repeats (DR3–5) and inverted repeats (IR6), but the preferred binding site in vitro is βDR4 with the half site sequence AGTTCA (7Blumberg B. Sabbagh Jr., W. Juguilon H. Bolado Jr., J. van Meter C.M. Ong E.S. Evans R.M. Genes Dev. 1998; 12: 3195-3205Crossref PubMed Scopus (819) Google Scholar). steroid and xenobiotic receptor SXR response element pregnane X receptor retinoid X receptor retinoic acid receptor liver X receptor dimethyl sulfoxide electrophoretic mobility shift assay. RXR is the common heterodimerization partner for many nuclear receptors, including the retinoic acid receptors (RARs), vitamin D receptor, liver X receptors (LXRs), peroxisome proliferator-activated receptors, and others (12Mangelsdorf D.J. Evans R.M. Cell. 1995; 83: 841-850Abstract Full Text PDF PubMed Scopus (2837) Google Scholar), and thus plays an important role in many diverse physiologic processes, including embryogenesis, calcium homeostasis, and lipid and glucose metabolism (13Ahuja H.S. Szanto A. Nagy L. Davies P.J. J. Biol. Regul. Homeost. Agents. 2003; 17: 29-45PubMed Google Scholar, 14Szanto A. Narkar V. Shen Q. Uray I.P. Davies P.J. Nagy L. Cell Death Differ. 2004; 11: S126-S143Crossref PubMed Scopus (223) Google Scholar). In addition, RXR forms homodimers, and RXR agonists, or rexinoids, are thought to activate transcription of target genes predominantly via these RXR/RXR dimers. However, in the context of different heterodimers, RXR can function either as a silent receptor that does not bind rexinoids (non-permissive dimers), as an active partner that binds rexinoids and activates transcription (permissive dimers), or even as an antagonistic partner that binds rexinoids and thus inhibits activation of transcription. For example, rexinoids stimulate transcription of peroxisome proliferator-activated receptor and LXR target genes through activation of peroxisome proliferator-activated receptor/RXR and LXR/RXR (15Mukherjee R. Davies P.J. Crombie D.L. Bischoff E.D. Cesario R.M. Jow L. Hamann L.G. Boehm M.F. Mondon C.E. Nadzan A.M. Paterniti Jr., J.R. Heyman R.A. Nature. 1997; 386: 407-410Crossref PubMed Scopus (576) Google Scholar). In contrast, binding of several rexinoids to farnesoid X receptor/RXR antagonizes its activation by farnesoid X receptor ligands via reduced DNA binding and coactivator recruitment (16Kassam A. Miao B. Young P.R. Mukherjee R. J. Biol. Chem. 2003; 278: 10028-10032Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). In the case of the SXR/RXR heterodimer, rexinoids have been shown to bind to SXR itself in vitro but only weakly activate transcription of SXR target genes in vivo (2Synold T.W. Dussault I. Forman B.M. Nat. Med. 2001; 7: 584-590Crossref PubMed Scopus (760) Google Scholar, 8Jones S.A. Moore L.B. Shenk J.L. Wisely G.B. Hamilton G.A. McKee D.D. Tomkinson N.C. LeCluyse E.L. Lambert M.H. Willson T.M. Kliewer S.A. Moore J.T. Mol. Endocrinol. 2000; 14: 27-39Crossref PubMed Scopus (543) Google Scholar). Nuclear receptors are targets of many post-translational modifications, including phosphorylation, sumoylation, ubiquitination, and acetylation, which critically affect their activity and often protein stability. For example, all-trans-retinoic acid triggers ubiquitination and proteasome-dependent degradation of its cognate receptors RARα and γ (17Kopf E. Plassat J.L. Vivat V. The H. P. C. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. E. P. C. J. 2002; PubMed Scopus Google Scholar, J. M. E. N. M. M. C. The H. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). of is dependent on its by protein and is for of receptor, of RARα inhibits its degradation (17Kopf E. Plassat J.L. Vivat V. The H. P. C. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. E. P. C. J. 2002; PubMed Scopus Google Scholar). all-trans-retinoic acid also triggers RXR degradation, and rexinoids stimulate degradation of both RARα and RXR via the J. M. E. N. M. M. C. The H. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar, D.L. G. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). of the receptor by also been shown to its degradation, that of protein can a factor receptor activity. been to a target of degradation as but in to RXR, and receptor, its rate was shown to in the of several that bind and activate that of receptor may its activation H. H. Hiramatsu Y. T. 2002; PubMed Scopus Google Scholar). In to degradation, nuclear receptors are targets of including which to their in a and their activity H. W. J. 2003; 83: PubMed Scopus Google Scholar). of the receptor by calpain a protein that as a active transcription factor that may play a role in K. S. M. 2006; PubMed Scopus Google Scholar, V. M. PubMed Scopus Google Scholar). of RXR been demonstrated in and the protein been shown to to the forms a heterodimer with the receptor and in response to the acid and the L. S. M. P. R. A. G. C. J. 2003; 17: PubMed Scopus Google Scholar, R. Y. S. H. Y. PubMed Scopus (26) Google Scholar). In the we have investigated the effect of two rexinoids, bexarotene (LGD1069/Targretin®) and LG100268, on SXR/RXR activity and is used as an of and in have on been in several in with of including R. J. L. P. C. B. A. V. R. J. Clin. 2006; PubMed Scopus Google Scholar), and have demonstrated activity in cells as well as in vivo of E.D. Heyman R.A. 1998; Google Scholar, Bischoff E.D. M.A. M.A. Heyman R.A. 56: Google Scholar, K. J.L. 2002; 11: Google Scholar, G. Y. Uray I. S. S. R. K. 2006; PubMed Scopus Google Scholar). Interestingly, bexarotene also been shown to the development of resistance to several drugs in and cells A. Clin. 2004; PubMed Scopus Google Scholar, Mol. 2005; PubMed Scopus Google Scholar, 2006; PubMed Scopus Google Scholar, 2004; PubMed Scopus Google Scholar). is a with high for RXR M.F. L. L. E. M. C.M. Davies Heyman R.A. Nadzan A.M. J. Med. Chem. 1995; PubMed Scopus Google but is not in We in agreement with previous reports S.A. Moore L.B. Shenk J.L. Wisely G.B. Hamilton G.A. McKee D.D. Tomkinson N.C. LeCluyse E.L. Lambert M.H. Willson T.M. Kliewer S.A. Moore J.T. Mol. Endocrinol. 2000; 14: 27-39Crossref PubMed Scopus (543) Google Scholar), that rexinoids can weakly activate transcription on their However, we also found that they rifampicin-induced activation of SXR response as well as of and CYP3A4 in to proteasome-dependent degradation of RXR, the rexinoids found to a rapid decrease in SXR protein which may explain why rexinoids, they bind to SXR with high in competition binding S.A. Moore L.B. Shenk J.L. Wisely G.B. Hamilton G.A. McKee D.D. Tomkinson N.C. LeCluyse E.L. Lambert M.H. Willson T.M. Kliewer S.A. Moore J.T. Mol. Endocrinol. 2000; 14: 27-39Crossref PubMed Scopus (543) Google Scholar), are not potent activators of transcription. on the which is a potent of SXR, not affect SXR stability. We thus that rexinoids may antagonize rifampicin-induced SXR activation by for binding to SXR and by degradation of the SXR/RXR transcription and and by and and and in and in the and for SXR and and and was for and in and and was Cell and cells in with in a cells in with or in with and a of The was and the cells with W. W. R. M. The for and as by the SXR RXR and the cells activity was the was was of of and CYP3A4 gene expression was the with gene expression and was used as the of SXR was the and with for of RXR and with of for and for by the cells in in and and by on and for to nuclear on for in and by for by and in and and on for was by for by the of protein in and by with by a The by enhanced was the with cells used was by in for by for to the The cells in and by a to DNA of was by for and the was in and with of protein DNA and with two different of of or of or RARα for with a of protein and protein and for SXR or protein DNA for RXR and The with to as in the and with in of and and by DNA was the was the with used to the the in the (1Geick A. Eichelbaum M. Burk O. J. Biol. Chem. 2001; 276: 14581-14587Abstract Full Text Full Text PDF PubMed Scopus (769) Google and used to the and was with of for and for of in vitro binding of nuclear as or in vitro expression the to the a βDR4 (7Blumberg B. Sabbagh Jr., W. Juguilon H. Bolado Jr., J. van Meter C.M. Ong E.S. Evans R.M. Genes Dev. 1998; 12: 3195-3205Crossref PubMed Scopus (819) Google Scholar, T. K. Evans R.M. Genes Dev. 7: PubMed Scopus Google was of nuclear was used for binding which was for in a and on and by In cells in a of and with by of the SXR sequence the the cells by of in vivo to or protein degradation by cells for and with was and cells in the or of for to For the of protein cells for to in the or of bexarotene by in and and of protein with protein for and the to with The with by of with in and and a with In as and in to a of for in the of and The was by of an of the in a and SXR was by In on and to The cells as with of the calpain the the of was a and and are shown as of the of in two or of with two and 2) with are by or and with or are by or activation of transcription by and cells with and and with rexinoids or or for expression of and protein in cells as is activation of and of in cells is of and CYP3A4 in cells is in by and to receptor the of SXR on the cells with bexarotene for bexarotene to the to SXR of or a to the transcriptional site of RXR binding to the and as in A. of RARα binding binding only to the of the RARα target gene of binding of nuclear and to a synthetic Nuclear cells as for and was as by or bexarotene of the binding of in vitro to the synthetic of the effect of rexinoids on SXR transcriptional activity, cells with and a the βDR4 (7Blumberg B. Sabbagh Jr., W. Juguilon H. Bolado Jr., J. van Meter C.M. Ong E.S. Evans R.M. Genes Dev. 1998; 12: 3195-3205Crossref PubMed Scopus (819) Google Scholar, T. K. Evans R.M. Genes Dev. 7: PubMed Scopus Google Scholar), and activity was with bexarotene or for bexarotene and weakly the but activation by rifampicin. an M.A. Pharmacol. 1997; PubMed Scopus Google Scholar), not activate transcription, activation by rifampicin. We that bexarotene and activation of transcription by a potent SXR in the effect of the bexarotene on expression of SXR target genes, expression was in cells with rifampicin, or both the level and the protein bexarotene expression of MDR1, a level rifampicin. However, bexarotene reduced the of by rifampicin, an antagonistic effect was in cells and in cells rifampicin-induced expression of SXR target was to reduced in the of bexarotene the used SXR or high and of the drugs or drug combination used in these a effect on the not of SXR/RXR to the SXR to binding of the SXR/RXR heterodimer to the in of by been shown to mediated by a element of the transcription site (1Geick A. Eichelbaum M. Burk O. J. Biol. Chem. 2001; 276: 14581-14587Abstract Full Text Full Text PDF PubMed Scopus (769) Google Scholar), we to as well as to the either or a level of receptor with the in cells was This was with but not with bexarotene rifampicin. of either the and or a not binding of either SXR or RXR to these of the of the was also an which binding to the of binding of nuclear cells with rifampicin, or both was also and enhanced binding by rifampicin, which was with the of despite the that bexarotene also caused enhanced binding the of the ability of in vitro SXR/RXR to bind to the synthetic in the or of bexarotene in binding of the drugs that in nuclear are to receptor DNA of SXR and RXR by is that rexinoids, including bexarotene and LG100268, stimulate degradation of the RXR as well as the RXR heterodimer and the receptor D.L. G. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). We thus the effect of these drugs on the levels of SXR and found a decrease in SXR protein levels in cells with either bexarotene or for In contrast, not the level of either SXR or RXR protein that the decrease in SXR was as as of bexarotene and was sustained for This was to the of bexarotene on the levels of RXR decrease of either SXR or RXR was on the level In bexarotene to have a effect on the transcription of the rexinoids or degradation of the SXR we in vivo of the degradation rate of was in the of or LG100268, and we found that both rexinoids a degradation rate the degradation rate of in was in both in the and of rexinoids, and the protein was not We the rate of of in cells by for to in the or of In to its on protein degradation, bexarotene not the rate We on to bexarotene SXR levels in cells protein been The cells with for by or Nuclear and and the levels of SXR and RXR The rate of SXR was to that of RXR, which for the However, in the of both a that of target genes is not for of receptor degradation We also SXR degradation in cells in the of rifampicin, but the SXR agonist not affect the rate with the that to of with not the level of SXR protein SXR in to in a to the mechanism of SXR degradation by we used The cells with for to of protein a of the was of the cells with reduced the ability of bexarotene to RXR, as but not SXR In contrast, which also inhibits S. Y. M. H. S. J. PubMed Scopus Google Scholar), degradation of both SXR and RXR The cells with a calpain in the or of was found to degradation of SXR, but not RXR that the two receptors are in by two that SXR can a target of calpain degradation, nuclear cells with as in in the or of calcium in the of both calpain and SXR was and a calpain activity in the cells was by of cells with bexarotene with the calpain This synthetic is that is calpain and thus calpain activity. We found that calpain activity was in cells with bexarotene for a mechanism by which the may stimulate degradation of of calpain bexarotene was also shown to induce a decrease of a nuclear calpain target M. S. I. P. M. Biol. Cell. 1995; Scopus Google Scholar). SXR is an important regulator of metabolism and transport of a wide range of is and by different ligands, drugs such as to such as have been shown to bind to SXR with high in competition binding bexarotene and in with for binding to SXR S.A. Moore L.B. Shenk J.L. Wisely G.B. Hamilton G.A. McKee D.D. Tomkinson N.C. LeCluyse E.L. Lambert M.H. Willson T.M. Kliewer S.A. Moore J.T. Mol. Endocrinol. 2000; 14: 27-39Crossref PubMed Scopus (543) Google Scholar). However, the that the rexinoids are potent in the transcriptional activity of SXR S.A. Moore L.B. Shenk J.L. Wisely G.B. Hamilton G.A. McKee D.D. Tomkinson N.C. LeCluyse E.L. Lambert M.H. Willson T.M. Kliewer S.A. Moore J.T. Mol. Endocrinol. 2000; 14: 27-39Crossref PubMed Scopus (543) Google Scholar). In the we that bexarotene and are weak activators of SXR transcription, and we also that the rexinoids transcriptional activation by both and SR12813, an antagonistic effect transcription of the gene in the of was with a level of receptor the response element by (1Geick A. Eichelbaum M. Burk O. J. Biol. Chem. 2001; 276: 14581-14587Abstract Full Text Full Text PDF PubMed Scopus (769) Google of SXR/RXR with response elements in the of the different drugs may in on by binding or may in receptor levels the on that binding of in vitro SXR/RXR to an SXR response element is by the of we that direct but in the We that the rexinoids the SXR protein degradation rate in a of the of transcription, which to the effect of rexinoids on RXR protein J. M. E. N. M. M. C. The H. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar, D.L. G. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). thus to that the SXR/RXR heterodimer is to the for degradation binding of an RXR However, we found that the was to degradation of SXR, In contrast, which inhibits the decrease in SXR but not affect the effect on RXR a of SXR by We that SXR can as a for calpain which a protein of the was on of SXR or in that is to rapid degradation and does not play a role in the to rexinoids may SXR degradation, calpain activity in cells with bexarotene was and in the calpain activity was found to This was by the that bexarotene was shown to decrease the protein level of nuclear calpain in a by Thus, we have shown for the that the SXR protein can via an in calpain activity, a level of to the of was shown to via the and several ligands activation found to H. H. Hiramatsu Y. T. 2002; PubMed Scopus Google Scholar). We not effect on SXR levels or in the of of the potent SXR rifampicin, that is not for activation of transcription. However, we that the rexinoid-induced of both SXR and RXR may important for the of these to activate transcription. the rexinoids and such as for binding to SXR may explain why transcription is in the of the two drugs in the of The are that the of target in response to calcium In the target a of and or H. W. J. 2003; 83: PubMed Scopus Google Scholar). activity is the level by calcium the of an as well as by by factor A. J. Cell Biol. 2002; PubMed Scopus Google Scholar). The mechanism of calpain activity in response to bexarotene is but that of target genes is not SXR is in a even in the of We suggest that bexarotene may activation of a that activates or may the level of bexarotene may calcium transcription in to SXR, are targets of calpain include as the nuclear receptors receptor and RXR V. M. PubMed Scopus Google Scholar, R. Y. S. H. Y. PubMed Scopus (26) Google Scholar, M. S. I. P. M. Biol. Cell. 1995; Scopus Google Scholar, M.H. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar). However, as opposed to the calpain of receptor and RXR, which K. S. M. 2006; PubMed Scopus Google Scholar, V. M. PubMed Scopus Google Scholar, L. S. M. P. R. A. G. C. J. 2003; 17: PubMed Scopus Google Scholar), the of SXR to to rapid degradation in cells we not the in vitro in of We that is a mechanism of SXR protein degradation that can by and the that rexinoids induce degradation of both SXR and RXR may explain why rexinoids not as potent activators of transcription. Because bexarotene to SXR degradation by calpain activity, we that the SXR rate in cells may also by the calpain activity and to SXR levels with calpain activity in different and an SXR levels and expression of a in liver S. M. T. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and to calpain activity the expression of an for to the ability of rexinoids, such as to antagonize SXR activation also to suppression of drug transport and metabolism by and as a of drug/drug interactions as well as development of drug

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