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

Abstract

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 δ-aminolevulinate dehydratase (δ-ALA-D) activity. δ-ALA-D catalyzes the condensation of two δ-aminolevulinic acid (δ-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 δ-ALA-D were examined. DMPS and DMSA caused a dose-dependent inhibition of hepatic δ-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 δ-ALA-D activity, in vitro. The mechanism of hepatic δ-ALA-D inhibition by Hg 2+–DMPS/DMSA and Cd 2+–DMPS/DMSA complexes involve the essential thiol groups of the enzyme.