EFFECT OF SPIRONOLACTONE ON DIMETHYL MERCURY TOXICITY - A POSSIBLE MOLECULAR MECHANISM

The protective activity of spironolactone (CAS 52-01-7) against dimeth y mercury intoxication was studied Dimethyl mercury increased serum gl utamate pyruvate transaminase (SGPT), serum bilirubin, blood urea nitr ogen (BUN), and caused impairment of the drug metabolic activity of ra t liver in vivo and in vitro. It also caused a severe neuropathy to th ese animals. Administration of spironolactone caused a reduction of di methyl mercury toxicity. It decreased the values of SGPT, bilirubin an d BUN, and restored the impaired drug metabolism caused by dimethyl me rcury. The neuropathy produced after administration of dimethyl mercur y was only mildly ameliorated by the treatment with spironolactone. Pr egnenolone-16a-carbonitrile (PCN), a potent microsomal enzyme inducer, had only a weak action, with the expected exception of the repair of the impaired drug metabolism of the liver. A mechanism of the protecti ve action of spironolactone against dimethyl mercury intoxication is p roposed. It is suggested that both the ability to induce drug metaboli zing enzymes, here demethylases, and the capacity to bind to the demet hylated metabolite of the organic mercurial, giving a non toxic, easil y excretable complex should coexist in the protective molecule.