Cadmium inhibits δ-aminolevulinate dehydratase from rat lung in vitro: Interaction with chelating and antioxidant agents

The effect of cadmium (Cd2+) on δ-aminolevulinate dehydratase (δ-ALA-D) activity from rat lung in vitro was investigated. δ-ALA-D activity, a parameter for metal intoxication, has been reported as a target of Cd2+ in different tissues. The protective effect of monotherapies with dithiol chelating (meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1-sulfonic acid (DMPS)) or antioxidant agents (ascorbic acid, diphenyl diselenide (PhSe)2, and N-acetylcysteine (NAC)) was evaluated. The effect of a combined therapy (dithiol chelating × antioxidant agent) was also studied. Zinc chloride (ZnCl2) and dithiothreitol (DTT) were used to investigate the mechanisms involved in cadmium, chelating and antioxidant effects on δ-ALA-D activity. Cadmium inhibited rat lung δ-ALA-D activity at low concentrations. DTT (3 mM), but not ZnCl2 (100 μM), protected the inhibition of enzyme activity caused by Cd2+. Chelating agents were not effective in restoring the enzyme activity. DMPS and DMSA presented inhibitory effect on enzyme activity. DTT restored the inhibition caused by both chelating agents, but ZnCl2 restored only the inhibitory effect induced by DMSA. These compounds caused a marked potentiation of δ-ALA-D inhibition induced by Cd2+. ZnCl2 did not restore inhibition of enzyme activity caused by Cd2+ plus chelating agents. Conversely, DTT restored the inhibition induced by Cd2+/DMSA, but not by Cd2+/DMPS. Antioxidants were not effective in ameliorating δ-ALA-D inhibition induced by Cd2+, whereas ascorbic acid potentiated the enzyme inhibition induced by this metal. A combined effect of Cd2+ × DMPS × (PhSe)2 and Cd2+ × DMPS × NAC was observed. There was no combined effect of Cd2+ × chelator × antioxidants when DMSA was used. This study demonstrated that Cd2+inhibited δ-ALA-D activity and chelating and antioxidant agents, alone or combined, did not restore the enzyme activity. In contrast, these compounds potentiated the inhibition induced by Cd2+ in rat lung.