Inhibition of biliary glutathione secretion by cyclosporine A in the rat: possible mechanisms and role in the cholestasis induced by the drug

Morán, Dominica; Buitrago, José Manuel González de; Fernández, Emilio; Galán, A.I.; Muñoz, Mauricio Pastor; Jiménez, Rafael

doi:10.1016/s0168-8278(98)80180-3

Cited by 42 publications

(61 citation statements)

References 40 publications

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supporting

confidence: 59%

“…A similar reaction has been noted in rats and may be related to a dose-and time-dependent decrease in biliary secretion of bile acids and glutathione (GSH) (Moran et al 1998). Cyclosporine A reduced both bile acid-dependent bile flow, and to a lesser extent bile acid-independent bile flow (BAIF) (Moran et al 1998). Competitive inhibition by cyclosporine A of the canalicular ATP-dependent bile salt export pump (Bsep) is believed to account for the bile aciddependent bile flow decline (Bohme et al 1994) and recently it has been shown that cyclosporine A can inhibit Bsep directly, thereby inducing cholestasis (Stieger et al 2000).…”

supporting

confidence: 58%

“…Its ATP-dependent excretion to the bile via Mrp2 is an important driving force for bile acid-independent bile flow. Rats treated with cyclosporine A have reduced GSH secretion into bile and bile acid-independent bile flow (Moran et al 1998), conjugated hyperbilirubinemia (Galan et al 1995), and increased lipid peroxidation (Galan et al 1999). In our study, both GCSlc and GCShc mRNA were down-regulated after cyclosporine A.…”

Section: Gsh Metabolising Enzymes and Mrp2mentioning

confidence: 99%

“…Competitive inhibition by cyclosporine A of the canalicular ATP-dependent bile salt export pump (Bsep) is believed to account for the bile aciddependent bile flow decline (Bohme et al 1994) and recently it has been shown that cyclosporine A can inhibit Bsep directly, thereby inducing cholestasis (Stieger et al 2000). Reduced hepatic content and reduced biliary secretion of GSH may partly explain the decrease in bile acid-independent bile flow (Moran et al 1998;Galan et al 1999). However, the mechanisms of these cholestatic changes are not known in detail.…”

mentioning

confidence: 99%

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Cholestasis and Regulation of Genes Related to Drug Metabolism and Biliary Transport in Rat Liver Following Treatment with Cyclosporine A and Sirolimus (Rapamycin)

Bramow¹,

Ott²,

Nielsen

et al. 2001

Pharmacology & Toxicology

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Cyclosporine A and sirolimus are used alone or in combination as immunosuppressants in organ transplantation. To elucidate hepatic side effects, we examined hepatic mRNA of proteins involved in biliary and hepatocellular transport of drugs, formation of glutathione (GSH) and drug metabolising cytochrome P-450 enzymes (CYPs) in rats treated orally for 2 weeks with cyclosporine A (15 mg/kg/day), sirolimus (0.4 mg/kg/day), their combination (same doses), or vehicle. Liver function tests (alanine aminotransferase, alkaline phosphatase, g-glutamyl transferase and bilirubin) in blood were then analysed as were hepatic mRNA levels of canalicular transport proteins (Mrp2, Bsep, Mdr1b and Mdr2), sinusoidal transport proteins (Ntcp, Oatp1 and Oatp2), GSH related enzymes (g-glutamylcysteine synthetase light (GCSlc) and heavy (GCShc) chain subunits and glutathione-S-transferase) and CYPs (CYP3A9, CYP1A2, CYP2E1 and CYP2BI/ II). Cyclosporine A caused moderate cholestatic changes in liver enzymes, which was synergistically exacerbated by sirolimus. The data suggest that the underlying mechanisms behind cholestasis were not totally identical in the different treatment regimens. Cholestasis secondary to cyclosporine A could be related to reduction in mRNA expression of GSH synthesising enzymes and Mrp2, leading to reduced protection against oxidative stress and reduced bile acid-independent bile flow. After sirolimus treatment, Mrp2 mRNA was also reduced together with reduced levels of most CYPs and increased Oatp2, possibly leading to accumulation of toxic metabolites in the hepatocytes. The enhanced cholestatic effect of the combination treatment could be related to reduced GSH synthesising enzymes and even more pronounced reduction in Mrp2 mRNA and increase of Oatp2 mRNA.

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supporting

confidence: 59%

supporting

confidence: 58%

Section: Gsh Metabolising Enzymes and Mrp2mentioning

confidence: 99%

mentioning

confidence: 99%

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Cholestasis and Regulation of Genes Related to Drug Metabolism and Biliary Transport in Rat Liver Following Treatment with Cyclosporine A and Sirolimus (Rapamycin)

Bramow¹,

Ott²,

Nielsen

et al. 2001

Pharmacology & Toxicology

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“…[64][65][66][67] It interferes with several hepatic processes, mainly bile formation, inducing a cholestatic syndrome in rats [68][69][70][71] and humans. 72 The cholestasis is caused by a reduction in canalicular bile flow 69 via inhibition of the ATP-dependent export carriers of bile salts in the hepatocyte canalicular membrane, impairment of bile formation dependent on the biliary secretion of glutathione, 70 and inhibition of the canalicular bile salt export pump. 71 Therefore, cyclosporine should be considered a cause of unexplained cholestasis in the transplant recipient.…”

Section: Cyclosporinementioning

confidence: 99%

Intrahepatic cholestasis after liver transplantation

Ben‐Ari

Pappo

Mor

2003

Liver Transplantation

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Cholestasis is a common sequela of liver transplantation. Although the majority of cases remain subclinical, severe cholestasis may be associated with irreversible liver damage, requiring retransplantation. Therefore, it is essential that clinicians be able to identify and treat the syndromes associated with cholestasis. In this review, we consider causes of intrahepatic cholestasis. These may be catego-

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