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Oral application of 1,7‐dimethylxanthine (paraxanthine) attenuates the formation of experimental cholestatic liver fibrosis

2011; Wiley; Volume: 41; Issue: 11 Linguagem: Inglês

10.1111/j.1872-034x.2011.00856.x

1872-034X

Ildikó Klemmer, Shintaro Yagi, O Gressner,

Liver Disease Diagnosis and Treatment

Aim: Several epidemiological studies suggest a beneficial effect of coffee consumption on the formation and progression of fibrogenic diseases, particularly of the liver. Recent data now point to a modulation of transforming growth factor‐β (TGF‐β) signaling by paraxanthine (1,7‐dimethylxanthine [1,7‐DMX]), the demethylated primary metabolite of caffeine Methods: Twenty adult Sprague–Dawley rats were bile duct ligated (BDL) or sham operated with or without concomitant oral 1,7‐DMX (1 mM) application. Serum was investigated by standard biochemical analysis, in‐house connective tissue growth factor (CTGF), enzyme linked immunosorbent assay (ELISA) or liquid chromatography‐mass spectrometry analysis. Liver tissue was stained using hematoxylin‐eosin (HE) and Sirius‐red staining. Whole liver lysates, primary rat hepatocytes (PC) and hepatic stellate cells (HSC) were investigated by CTGF, and total Smad2/3 Western blot analysis, CTGF reporter gene assay or an in‐house malondialdehyde ELISA. Results: The in vitro 50% inhibitory dose (ID50) of 1,7‐DMX was 0.95 mM by for CTGF promoter activity and protein expression in PC and 1.25 mM for protein expression in HSC. Oral 1,7‐DMX application (1 mM) attenuated cholestatic hepatocellular injury in vivo as determined by biochemical serum analysis and reduced intercellular collagen deposition in the cholestatic rat liver (HE‐ and Sirius‐red staining). Western Blot analysis of whole liver lysates revealed a reduction of intrahepatic concentrations of Smad2/3 and CTGF following oral 1,7‐DMX intake. However, serum CTGF concentrations were not reduced in 1,7‐DMX treated BDL rats. Oral 1,7‐DMX furthermore led to a reduction of intrahepatic lipid peroxidation (malondialdehyde concentrations) as markers of oxidative stress in BDL rats. Conclusion: Our pilot study warrants further studies of 1,7‐DMX as a potential new drug to fight fibrotic processes, not just of the liver.