Session Speaker

Identification of Paraxanthine as the Most Potent Inhibitor of Hepatocellular Connective Tissue Growth Factor Expression Among the Three Primary Caffeine Metabolites
Olav A. Gressner, Birgit Lahme, Monika Siluschek, Axel M. Gressner
Germany

Background: Recently, we identified hepatocytes as the major cellular source of profibrogenic connective tissue growth factor (CTGF/CCN2) in the liver. Based on reports of a hepatoprotective effect of coffee consumption, we were the first to give evidence that caffeine suppresses TGF-β dependent and - independent CTGF expression in hepatocytes, thus suggesting this xanthine-alkaloid as a potentially therapeutic agent.

Aim: This study aims at comparing the inhibitory capacities of caffeine and its three demethylated derivates paraxanthine, theophylline and theobromine on hepatocellular CTGF expression.

Results: Our data suggest paraxanthine, in particular if combined with theophylline, as the most important pharmacological repressor of hepatocellular CTGF expression with an ID50 of 1.15mM, i.e. 3.84-fold lower than what is observed for caffeine. At the toxicological threshold concentration of 1mM for paraxanthine, we observe an inhibition of hepatocellular CTGF synthesis by 44%, which is strongly reverted in the presence of the specific competitive cAMP inhibitor Rp-cAMP. Furthermore, CTGF protein expression induced by various concentrations of TGF-β (0.13 - 1ng/ml) is still reduced by on average 27%/45% in the presence of paraxanthine (1.25mM/2.5mM).

Conclusion: Our data provide an evidence-based suggestion of the caffeine derived metabolite paraxanthine as potentially powerful antifibrotic drug by its inhibitory effect on (hepatocellular) CTGF synthesis.