Cyclosporine a Hepatotoxicity: Effect of Prolonged Treatment With Cyclosporine on Biliary Lipid Secretion in the Rat

Galán, A.I.; Fernández, Emilio; Morán, Dominica; Muñoz, Mauricio Pastor; Jiménez, Rafael

doi:10.1111/j.1440-1681.1995.tb01991.x

Cited by 44 publications

(32 citation statements)

References 20 publications

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“…Although no remarkable histological changes were observed in the cyclosporine A-treated group (table 4), functional impairment of cells in the biliary canaliculi appeared to be induced, as suggested by the increase in serum total bilirubin and total bile acids with cyclosporine A at both 10 and 20 mg/kg. There have also been reports that administration of cyclosporine A at the same doses resulted in significant decrease in bile flow and bile acid secretion [14][15][16]. Therefore, cyclosporine A was considered to have produced cholestasis as with 4,4¢-methylene dianiline, a-naphthylisothiocyanate and bile duct ligation.…”

Section: Discussionmentioning

confidence: 99%

“…Three groups of animals received repeated intraperitoneal administration of cyclosporine A (10 or 20 mg/kg/day for 14 days, n ¼ 5) or vehicle (saline solution, n ¼ 5) as control-2. The dose and period of administration of cyclosporine A were selected based on previous studies [14][15][16]. Other groups of rats received a single oral administration of 4,4¢-methylene dianiline (75 mg/kg, n ¼ 5), a-naphthylisothiocyanate (75 mg/kg, n ¼ 5) or vehicle (0.5% methylcellulose solution, n ¼ 5) as control-3.…”

Section: Methodsmentioning

confidence: 99%

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Identification of Urinary Biomarkers Useful for Distinguishing a Difference in Mechanism of Toxicity in Rat Model of Cholestasis

Ishihara

Katsutani

Asai

et al. 2009

Basic Clin Pharma Tox

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This 1 H nuclear magnetic resonance metabonomics study was aimed to determine urinary biomarkers of cholestasis resulting from inhibition of biliary secretion of bile or obstruction of bile flow. To inhibit biliary secretion of bile, cyclosporine A was administered to male Sprague-Dawley rats. Obstruction of bile flow was induced by administration of 4,4¢-methylene dianiline, a-naphthylisothiocyanate or bile duct ligation. Clinical pathological and histopathological examinations were performed to confirm cholestatic injury and 1 H nuclear magnetic resonance spectral data for urine samples were analysed to determine similarities and differences in profiles of metabolites using the Spotfire Ò . In cyclosporine A-treated groups, serum total bilirubin and bile acid were significantly increased but no remarkable hepatic histopathological-changes were observed. In 4,4¢-methylene dianiline-, a-naphthylisothiocyanate-and bile duct ligationtreated groups, serum alkaline phosphatase, c-glutamyltranspeptidase and total bilirubin levels increased significantly, and hepatic histopathological-changes were observed. On urinary 1 H nuclear magnetic resonance spectral analysis, area intensities derived from 0.66 to 1.90 ppm were decreased by cyclosporine A, whereas they were increased by other treatments. These metabolites were identified using the NMR suite Ò as bile acids, branched-chain amino acids, n-butyrate, propionate, methyl malonate and valerate. These metabolites were further investigated by K-means clustering analysis. The cluster of these metabolites is considered to be altered by cholestasis. We conclude that bile acids, valine and methyl malonate have a possibility to be urinary cholestatic biomarkers, which distinguish a difference in mechanism of toxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Identification of Urinary Biomarkers Useful for Distinguishing a Difference in Mechanism of Toxicity in Rat Model of Cholestasis

Ishihara

Katsutani

Asai

et al. 2009

Basic Clin Pharma Tox

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“…3 Bile flow and secretion of bile acid, cholesterol, and phospholipids are reduced during CsA treatment. 4,17 In the liver, most of the blood flow enters through the portal vein, and the resistance changes are thought to occur in the microvascular anastomosis of the portal and hepatic veins, known as hepatic sinusoids. Shah et al 19 have recently reported that in rat liver, eNOS is abundantly expressed in the sinusoidal endothelial cells and that these cells respond to shear stress by increasing NO release.…”

Section: Sánchez-lozada Et Al Nos Mrna Expression In Csa Toxicity 645mentioning

confidence: 99%

“…3,4 In isolated perfused rat liver, CsA administration produced a dose-dependent reduction of bile flow, increased the release of cytosolic and mitochondrial enzymes, and decreased oxygen consumption. 3 High blood levels of CsA in human allograft recipients have been associated with an increase in ␥-glutamyl transpeptidase, a liver enzyme that correlates with hepatotoxicity.…”

mentioning

confidence: 99%

Nifedipine Prevents Changes in Nitric Oxide Synthase mRNA Levels Induced by Cyclosporine

Sánchez‐Lozada

Gamba²,

Bolio³

et al. 2000

Hypertension

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Abstract-Cyclosporine toxicity mainly affects kidney and liver function. We have previously shown that cyclosporine nephrotoxicity alters kidney nitric oxide synthase mRNA pattern of expression. To determine if nitric oxide synthase expression changes are mediated directly by cyclosporine or by secondary hemodynamic alterations induced by cyclosporine, we evaluated if these effects are tissue specific and if nifedipine-induced vasodilation prevents these alterations. Uninephrectomized Wistar rats treated for 7 days with olive oil, cyclosporine (30 mg/kg), nifedipine (3 mg/kg), and nifedipineϩcyclosporine were studied. In vehicle and cyclosporine groups, the gene expression of the neuronal, inducible, and endothelial nitric oxide synthases in cerebellum, heart, intestine, liver, renal cortex, and medulla was evaluated. The administration of cyclosporine was associated with nephrotoxicity and hepatotoxicity, increased endothelial nitric oxide synthase mRNA levels in renal cortex and liver, and a decrease in inducible nitric oxide synthase and neuronal nitric oxide synthase in renal medulla. The mRNA levels of the 3 nitric oxide synthase isoforms were not affected in any other tissue. Nifedipine did not alter nitric oxide synthase expression in the control group but prevented changes associated with cyclosporine. These results suggest that cyclosporine-induced changes in the pattern of expression of the nitric oxide synthases may be secondary to its hemodynamic effects. (Hypertension. 2000;36:642-647.)Key Words: nitric oxide Ⅲ liver Ⅲ hypertension Ⅲ cyclosporine C yclosporine (CsA) is an immunosuppressor drug. Despite its beneficial effects, however, long-term use is frequently associated with hypertension, nephrotoxicity, and hepatotoxicity.Nephrotoxicity is the most common complication associated with CsA therapy. 1 It is characterized by renal vasoconstriction that induces a decrease in renal plasma flow and glomerular filtration rate. This side effect is usually reversible when CsA dose is reduced. However, even with normal blood levels or during long-term dosage, CsA can produce chronic hypertension and can be the cause of irreversible impairment of renal function. 2 The mechanism by which CsA induces hypertension remains unknown.Hepatotoxicity is a less common side effect, which is characterized by cholestasis and metabolic disturbances. 3,4 In isolated perfused rat liver, CsA administration produced a dose-dependent reduction of bile flow, increased the release of cytosolic and mitochondrial enzymes, and decreased oxygen consumption. 3 High blood levels of CsA in human allograft recipients have been associated with an increase in ␥-glutamyl transpeptidase, a liver enzyme that correlates with hepatotoxicity. 5 In one study, hepatic abnormalities developed in up to 32% of patients with endogenous uveitis treated with CsA. 6 CsA toxicity has been attributed to an imbalance of vasoactive substance release. 1 Recent studies have shown that nitric oxide (NO) is increased during CsA administration by a mechanism th...

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“…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%

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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Cyclosporine a Hepatotoxicity: Effect of Prolonged Treatment With Cyclosporine on Biliary Lipid Secretion in the Rat

Cited by 44 publications

References 20 publications

Identification of Urinary Biomarkers Useful for Distinguishing a Difference in Mechanism of Toxicity in Rat Model of Cholestasis

Identification of Urinary Biomarkers Useful for Distinguishing a Difference in Mechanism of Toxicity in Rat Model of Cholestasis

Nifedipine Prevents Changes in Nitric Oxide Synthase mRNA Levels Induced by Cyclosporine

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

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