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Titolo:
Cholestasis and regulation of genes related to drug metabolism and biliarytransport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin)
Autore:
Bramow, S; Ott, P; Nielsen, FT; Bangert, K; Tygstrup, N; Dalhoff, K;
Indirizzi:
Rigshosp, Dept Clin Pharmacol Q 7642, DK-2200 Copenhagen N, Denmark Rigshosp Copenhagen Denmark N acol Q 7642, DK-2200 Copenhagen N, Denmark Rigshosp, Dept Hepatol A, DK-2100 Copenhagen, Denmark Rigshosp Copenhagen Denmark DK-2100 patol A, DK-2100 Copenhagen, Denmark Rigshosp, Dept Clin Biochem KB, DK-2100 Copenhagen, Denmark Rigshosp Copenhagen Denmark DK-2100 chem KB, DK-2100 Copenhagen, Denmark Odense Univ Hosp, Dept Nephrol Y, Lab Nephropathol, DK-5000 Odense, Denmark Odense Univ Hosp Odense Denmark DK-5000 opathol, DK-5000 Odense, Denmark
Titolo Testata:
PHARMACOLOGY & TOXICOLOGY
fascicolo: 3, volume: 89, anno: 2001,
pagine: 133 - 139
SICI:
0901-9928(200109)89:3<133:CAROGR>2.0.ZU;2-#
Fonte:
ISI
Lingua:
ENG
Soggetto:
SALT EXPORT PUMP; ORGANIC ANION; RENAL-TRANSPLANTATION; P-GLYCOPROTEIN; CDNA CLONING; MDR2 GENE; EXPRESSION; INHIBITION; MECHANISMS; ACID;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
42
Recensione:
Indirizzi per estratti:
Indirizzo: Dalhoff, K Rigshosp, Dept Clin Pharmacol Q 7642, Tagensvej 20, DK-2200 Copenhagen N, Denmark Rigshosp Tagensvej 20 Copenhagen Denmark N penhagen N, Denmark
Citazione:
S. Bramow et al., "Cholestasis and regulation of genes related to drug metabolism and biliarytransport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin)", PHARM TOX, 89(3), 2001, pp. 133-139

Abstract

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, alkalinephosphatase, gamma -glutamyl transferase and bilirubin) in blood were thenanalysed as were hepatic mRNA levels of canalicular transport proteins (Mrp2, Bsep, Mdr1b and Mdr2), sinusoidal transport proteins (Ntcp, Oatp1 and Oatp2), GSH related enzymes (gamma -glutamylcysteine synthetase light (GCSIc) 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 07/07/20 alle ore 12:41:53