Cadmium inhibits delta-aminolevulinate dehydratase from rat lung in vitro: interaction with chelating and antioxidant agents.
The effect of cadmium (Cd(2+)) on delta-aminolevulinate dehydratase (delta-ALA-D) activity from rat lung in vitro was investigated. delta-ALA-D activity, a parameter for metal intoxication, has been reported as a target of Cd(2+) 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 chelatingxantioxidant agent) was also studied. Zinc chloride (ZnCl(2)) and dithiothreitol (DTT) were used to investigate the mechanisms involved in cadmium, chelating and antioxidant effects on delta-ALA-D activity. Cadmium inhibited rat lung delta-ALA-D activity at low concentrations. DTT (3mM), but not ZnCl(2) (100microM), protected the inhibition of enzyme activity caused by Cd(2+). 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 ZnCl(2) restored only the inhibitory effect induced by DMSA. These compounds caused a marked potentiation of delta-ALA-D inhibition induced by Cd(2+). ZnCl(2) did not restore inhibition of enzyme activity caused by Cd(2+) plus chelating agents. Conversely, DTT restored the inhibition induced by Cd(2+)/DMSA, but not by Cd(2+)/DMPS. Antioxidants were not effective in ameliorating delta-ALA-D inhibition induced by Cd(2+), whereas ascorbic acid potentiated the enzyme inhibition induced by this metal. A combined effect of Cd(2+)xDMPSx(PhSe)(2) and Cd(2+)xDMPSxNAC was observed. There was no combined effect of Cd(2+)xchelatorxantioxidants when DMSA was used. This study demonstrated that Cd(2+)inhibited delta-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 Cd(2+) in rat lung.
Luchese
Cristiane
C
Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, CEP 97105-900, RS, Brazil.
Zeni
Gilson
G
Rocha
João B T
JB
Nogueira
Cristina W
CW
Santos
Francielli W
FW
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D001555:Benzene Derivatives / Q000494:pharmacology; D019256:Cadmium Chloride / Q000494:pharmacology*; D002614:Chelating Agents / Q000494:pharmacology*; D002712:Chlorides / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004785:Environmental Pollutants / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D016566:Organoselenium Compounds / Q000494:pharmacology; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D004113:Succimer / Q000494:pharmacology; D014494:Unithiol / Q000494:pharmacology; D017967:Zinc Compounds / Q000494:pharmacology
D000975:Antioxidants; D001555:Benzene Derivatives; D002614:Chelating Agents; D002712:Chlorides; D004338:Drug Combinations; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D016566:Organoselenium Compounds; D017967:Zinc Compounds; C061132:diphenyldiselenide; D014494:Unithiol; C016837:zinc chloride; D004113:Succimer; D000623:Porphobilinogen Synthase; D019256:Cadmium Chloride; D001205:Ascorbic Acid; D004229:Dithiothreitol; D000111:Acetylcysteine