2,3-Dimercaptopropane-1-sulfonic acid and meso-2,3-dimercaptosuccinic acid increase mercury- and cadmium-induced inhibition of delta-aminolevulinate dehydratase

Compounds derived from Dimercaprol, such as meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1-sulfonic acid (DMPS), are becoming common agents for treating humans exposed to heavy metals. Heavy metals such as Pb(2+), Hg(2+) and Cd(2+) can inhibit delta-aminolevulinate dehydratase (delta-ALA-D) activity. Delta-ALA-D catalyzes the condensation of two delta-aminolevulinic acid (delta-ALA) molecules with the formation of porphobilinogen, a heme precursor. The effects of DMSA and DMPS alone or in combination with Cd(2+), Hg(2+), or Pb(2+) on hepatic delta-ALA-D were examined. DMPS and DMSA caused a dose-dependent inhibition of hepatic delta-ALA-D. In the presence of Hg(2+) or Cd(2+) the inhibitory potency of DMPS increased. Similarly, the inhibitory effects of Hg(2+) and Cd(2+) were markedly increased in the presence of DMSA. In contrast, the inhibitory effect of DMPS was not changed by inclusion of Pb(2+). As observed with DMSA, Zn(2+) did not modified the inhibitory effect of DMPS. Data of the present report support the idea that the complexes formed (metals-DMSA or DMPS) were more inhibitory than the metal (Hg(2+) and Cd(2+)) or the chelating agent alone to the hepatic delta-ALA-D activity, in vitro. The mechanism of hepatic delta-ALA-D inhibition by Hg(2+)-DMPS/DMSA and Cd(2+)-DMPS/DMSA complexes involve the essential thiol groups of the enzyme.