Modulation of thiol homeostasis induced by a novel H2S-releasing compound

Recently, the physiological function of hydrogen sulfide (H2S) has been discovered and a potential therapeutic use of this gas for the treatment of diseases characterized by its altered concentrations has been suggested. A possible approach for a therapeutic administration of H2S is represented by molecules able to release H2S in a controlled manner, mimicking what happens physiologically. Dithiolethiones have been found to behave as H2S donors in physiological conditions. N-Acetylcysteine (NAC) is under investigation as potential therapeutic agent against several different pathologies characterized by the occurrence of oxidative stress and a decrease in GSH although results deriving from large, multi-center, prospective clinical trials are on most case contradictory and inconclusive. It is possible that the scarce efficacy of NAC is due to its low oral bioavailability (about 8%). We have recently observed that both dithiolethione containing molecules and the derivative of NAC, N-acetylcysteine ethylester (NACET) are able to significantly reduce circulating and tissue levels of hyperomocysteinemia (hCys), probably via an increase of the thiol to disulfide ratio in extracellular fluids. Mild hCys is considered an independent risk factor for cardiovascular and cerebrovascular disease. Starting from these observations, we synthesized new dithiolethione–cysteine hybrids (ACS94, ACS96, ACS97) with the assumption that they could have synergic effect in reducing plasma hCys, as well (by tissue glutathione increase) correcting the redox imbalance process present in several diseases. The effects on thiols pool in different organs and in plasma, after iv or oral administration of NAC (10mg/kg) or equimolar ACS94 to healthy rats and after ip administration of paracetamol (as a model of hepatic toxicity), have been investigated. The results clearly indicate that ACS94 protects from paracetamol induced hepatic toxicity better than NAC and that ACS94 prevents paracetamol induced thiol depletion in kidney and liver. In addition a more significant decrease of hCys compared to NAC, was observed in some rat target organs and in plasma.