Abstract
We studied the effect of cyclosporin A (CyA) on liver plasma membrane (LPM) composition, fluidity, and functions and on hepatic glutathione (GS) and oxidative status. We also evaluated the ability ofS-adenosylmethionine (SAMe) to antagonize the CyA-induced disturbances in rats. The animals were randomly divided into four groups and treated daily with saline, CyA vehicle, CyA, and SAMe plus CyA, respectively, for 1 week. Bile, blood, and liver samples and LPM vesicles were obtained at the end of the treatments. CyA-induced cholestasis was associated with alterations in LPM composition and fluidity. The contents of total phospholipids, phosphatidylcholine, and proteins were decreased and cholesterol and the cholesterol/phospholipid molar ratio increased. Na+,K+-ATPase activity was decreased, whereas those of 5′-nucleotidase, Mg2+-ATPase, and γ-glutamyltransferase increased. The hepatic contents of proteins and GS and the reduced/oxidized glutathione molar ratio were decreased and hepatic malondialdehyde increased. SAMe cotreatment 1) significantly improved or abolished the CyA-induced changes in LPM fluidity and composition and the changes in the activity of the carrier and enzymes tested, 2) counteracted the hepatic depletion of GS and proteins caused by CyA and normalized the reduced/oxidized glutathione ratio, and, as expected, 3) prevented cholestasis and the inhibitory effect of CyA on hepatobiliary transport of the major bile components. We conclude that CyA-induced cholestasis and hepatotoxicity in the rat is associated with changes in LPM composition and fluidity, liver GS depletion, and oxidative stress. SAMe cotreatment significantly improves or totally protects against these hepatotoxic effects.
Footnotes
-
Send reprint requests to: Prof. Rafael Jiménez, M.D., Departamento de Fisiologı́a y Farmacologı́a, Edificio Departamental, Campus Miguel de Unamuno, 37007-Salamanca, Spain. E-mail: rajim{at}gugu.usal.es
-
↵1 The work was supported in part by the Dirección General de Ensen̄anza Superior e Investigación Ciertifica (Project PM-0149) and Junta de Castilla y León (Project SA57/97).
- Abbreviations:
- LPM
- liver plasma membrane
- BA
- bile acids
- CHO
- cholesterol
- CyA
- cyclosporin A
- γ-GT
- γ-glutamyltransferase
- GS
- glutathione
- GSH
- reduced glutathione
- GSSG
- oxidized glutathione
- MDA
- malondialdehyde
- PC
- phosphatidylcholine
- PE
- phosphatidylethanolamine
- PHO
- phospholipid
- SAMe
- S-adenosyl-l-methionine
- Received October 26, 1998.
- Accepted March 25, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|