Effect of spironolactone on dimethyl mercury toxicity. A possible molecular mechanism.
The protective activity of spironolactone (CAS 52-01-7) against dimethyl mercury intoxication was studied. Dimethyl mercury increased serum glutamate pyruvate transaminase (SGPT), serum bilirubin, blood urea nitrogen (BUN), and caused impairment of the drug metabolic activity of rat liver in vivo and in vitro. It also caused a severe neuropathy to these animals. Administration of spironolactone caused a reduction of dimethyl mercury toxicity. It decreased the values of SGPT, bilirubin and BUN, and restored the impaired drug metabolism caused by dimethyl mercury. The neuropathy produced after administration of dimethyl mercury was only mildly ameliorated by the treatment with spironolactone. Pregnenolone-16 alpha-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 protective action of spironolactone against dimethyl mercury intoxication is proposed. It is suggested that both the ability to induce drug metabolizing enzymes, here demethylases, and the capacity to bind to the demethylated metabolite of the organic mercurial, giving a non toxic, easily excretable complex should coexist in the protective molecule.
Kourounakis
P N
PN
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Thessaloniki, Greece.
Rekka
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E
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D005037:Ethylmorphine-N-Demethylase / Q000378:metabolism; D005260:Female; D008767:Methylmercury Compounds / Q000037:antagonists & inhibitors* / Q000633:toxicity; D009153:Mutagens / Q000633:toxicity*; D009422:Nervous System Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D009443:Neuritis / Q000139:chemically induced / Q000517:prevention & control; D009929:Organ Size / Q000187:drug effects; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013148:Spironolactone / Q000494:pharmacology*; D015049:Zoxazolamine / Q000494:pharmacology
D008767:Methylmercury Compounds; D009153:Mutagens; D011285:Pregnenolone Carbonitrile; D013148:Spironolactone; D015049:Zoxazolamine; C073972:dimethyl mercury; D005037:Ethylmorphine-N-Demethylase; D000410:Alanine Transaminase; D001663:Bilirubin