Comparison of Rifampicin With Phenobarbitone for Treatment of Pruritus in Biliary Cirrhosis

Bachs, L.; Elena, Montserrat; Parés, Albert; Piera, Carlos; Rodés, Joan

doi:10.1016/s0140-6736(89)91608-5

Cited by 215 publications

(123 citation statements)

References 21 publications

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“…Thus PXR plays a central role in coordinated regulation of bile acid homeostasis and drug metabolism. This may be the mechanism for using rifampicin and steroids to treat pruritus of intrahepatic cholestasis and primary biliary cirrhosis (1,12). Efficacious PXR agonists may be developed for treating these chronic liver diseases.…”

Section: Discussionmentioning

confidence: 99%

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Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7α-hydroxylase gene transcription

Li¹,

Chiang²

2005

American Journal of Physiology-Gastrointestinal and Liver Physi

192

179

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-Bile acids, steroids, and drugs activate steroid and xenobiotic receptor pregnane X receptor (PXR; NR1I2), which induces human cytochrome P4503A4 (CYP3A4) in drug metabolism and cholesterol 7␣-hydroxylase (CYP7A1) in bile acid synthesis in the liver. Rifampicin, a human PXR agonist, inhibits bile acid synthesis and has been used to treat cholestatic diseases. The objective of this study is to elucidate the mechanism by which PXR inhibits CYP7A1 gene transcription. The mRNA expression levels of CYP7A1 and several nuclear receptors known to regulate the CYP7A1 gene were assayed in human primary hepatocytes by quantitative real-time PCR (Q-PCR). Rifampicin reduced CYP7A1 and small heterodimer partner (SHP; NR02B) mRNA expression suggesting that SHP was not involved in PXR inhibition of CYP7A1. Rifampicin inhibited CYP7A1 reporter activity and a PXR binding site was localized to the bile acid response element-I. Mammalian two-hybrid assays revealed that PXR interacted with hepatic nuclear factor 4␣ (HNF4␣, NR2A1) and rifampicin was required. Coimmunoprecipitation assay confirmed PXR interaction with HNF4␣. PXR also interacted with peroxisome proliferator-activated receptor ␥ coactivator (PGC-1␣), which interacted with HNF4␣ and induced CYP7A1 gene transcription. Rifampicin enhanced PXR interaction with HNF4␣ and reduced PGC-1␣ interaction with HNF4␣. Chromatin immunoprecipitation assay showed that PXR, HNF4␣, and PGC-1␣ bound to CYP7A1 chromatin, and rifampicin dissociated PGC-1␣ from chromatin. These results suggest that activation of PXR by rifampicin promotes PXR interaction with HNF4␣ and blocks PGC-1␣ activation with HNF4␣ and results in inhibition of CYP7A1 gene transcription. Rifampicin inhibition of bile acid synthesis may be a protective mechanism against drug and bile acid-induced cholestasis.bile acid synthesis; gene regulation; nuclear receptors; peroxisome proliferator-activated receptor ␥ coactivator BILE ACID FEEDBACK INHIBITS bile acid synthesis by inhibiting the transcription of cholesterol 7␣-hydroxylase (CYP3A4), the rate-limiting enzyme in the bile acid biosynthetic pathway. This tightly regulated feedback mechanism is necessary because bile acids are highly toxic and cholesterol is needed for maintaining cellular structure and function. Recent studies (4) have revealed that bile acid feedback has far-reaching impacts on liver metabolism; it not only regulates bile acid synthesis in the digestive system but also regulates cholesterol, lipoprotein, triglyceride, and glucose metabolisms. The discovery that lithocholic acid (LCA) is an endogenous ligand for pregnane X receptor (PXR) suggests that bile acids may also regulate drug metabolism in the liver and intestine by induction of CYP450 enzymes (27, 34). PXR and its human ortholog steroid and xenobiotic receptor (SXR) induce the CYP3A, CYP2B, and CYP2C families of steroid-and drug-metabolizing enzymes in the liver and intestine (17). Despite the high-sequence identity in the ligand-binding domain between human and mouse PXR, they are very differ...

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Section: Discussionmentioning

confidence: 99%

“…Rifampicin has been used to treat pruritus of intrahepatic cholestasis and primary biliary cirrhosis (1,12). Rifampicin induces 6-hydroxylation of bile acids by CYP3A4.…”

mentioning

confidence: 99%

Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7α-hydroxylase gene transcription

Li¹,

Chiang²

2005

American Journal of Physiology-Gastrointestinal and Liver Physi

192

179

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“…Induction of Sult2a1 has been suggested to protect against the toxicity of LCA and might represent a target strategy for the treatment of cholestasis and colon cancer (Sonoda et al, 2002). In fact, rifampicin, a PXR ligand in humans, has been reported to be useful in treating cholestasis, which might be in part due to Sult2a1 induction (Bachs et al, 1989;Cancado et al, 1998;Sonoda et al, 2002). The higher expression of Sult2a1 in female than male mice is thought to contribute to the fact that female farnesoid X receptor-null mice are less susceptible to lithocholic acid toxicity than male mice (Sinal et al, 2000;Kitada et al, 2003;Zhang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Sulfotransferase Enzymes by Prototypical Microsomal Enzyme Inducers in Mice

Alnouti

Klaassen

2007

J Pharmacol Exp Ther

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“…Elevated levels of 6-hydroxylated bile acids are also observed in the urine of healthy subjects treated with the PXR ligand rifampicin (38). Interestingly, rifampicin has been used successfully in the treatment of pruritus associated with intrahepatic cholestasis and, in some instances, has been reported to induce remission of cholestasis (39)(40)(41). The molecular basis for these clinical effects has remained obscure.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

Staudinger

Goodwin

Jones

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

1,219

1,099

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The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16␣-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7␣-hydroxylase (Cyp7a1) and the Na ؉ -independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.

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Comparison of Rifampicin With Phenobarbitone for Treatment of Pruritus in Biliary Cirrhosis

Cited by 215 publications

References 21 publications

Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7α-hydroxylase gene transcription

Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7α-hydroxylase gene transcription

Regulation of Sulfotransferase Enzymes by Prototypical Microsomal Enzyme Inducers in Mice

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

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