INFLUENCE OF ACIDOSIS ON ESSENTIAL PROTEIN THIOLS-MEDIATED GLUTATHIONE PEROXIDASE MIMICRY OF DIPHENYL DISELENIDE

Abstract

t is a common knowledge among organoselenium experts that diphenyldiselenide (DPDS) exhibit glutathione peroxidase (GPx) mimetic property. However, reports have indicated that its toxicity on thiol-enzymes may be associated with its classical GPx mimetic catalytic antioxidant mechanism. However, the influence of pH on the activity of these thiol-enzymes vis-à-vis the GPx mimicry of DPDS is yet to be clarified. In this study, the antioxidant effect of diphenyldiselenide was tested in brain and liver homogenate previously assaulted with Fe 2+ in the presence and absence of iodoacetamide (IA) both at physiological pH and under condition of acidosis (pH 7.4 - 4.4). Furthermore, the effect of either acidosis or DPDS or combination of both was tested on the activity of the sulphydryl enzymes, cerebral sodium pump (Na + /K + -ATPase) and hepatic delta aminolevulinatedehydratase (δ-ALAD) in the presence of mono- and dithiols. Finally, rats were administered FeSO 4 (30mg/kg body weight) and DPDS (10 mg/kg body weight) for 20 days. Thereafter, the redox status, as well as the activities of Na + /K + -ATPase and δ-ALAD was evaluated in the absence and presence of the mono- and dithiols. The results indicated that irrespective of the pH, IA reduced the inhibitory effect of DPDS against the formation of Fe 2+ -mediated aldehydic product of lipid peroxidation. Also, while acidosis (pH < 7.0) has no marked effect on the activity of Na + /K + -ATPase, it markedly inhibited the activity of δ-ALAD at pH < 6.4. However, DPDS inhibited the activity of Na + /K + -ATPase irrespective of the pH, and inhibited the activity of δ- ALAD at pH ≥ 6.4. Also, while Fe 2+ evoked increased oxidative stress markers in vivo, DPDS markedly reversed this effect. Also, the activities of both Na + /K + -ATPase and δ-ALAD that were previously inhibited in the Fe 2+ treated groups were restored in the presence of the exogenous mono- and dithiols. Consequently, considering the fact that IA blocks the antioxidant action of DPDS at all pH tested, and that DPDS inhibited the activities of sodium pump and δ-ALAD at physiological pH and acidic pH, it is therefore reasonable to partly conclude that DPDS may depend on the thiols of sulphydryl enzymes to effect its GPx mimicry at physiologically relevant pH and in cases of acidosis.