Methyl mercury and selenium interaction in relation to mouse kidney gamma-glutamyltranspeptidase, ultrastructure, and function.
The effects of methyl mercury (CH3Hg) and selenium (Se) on renal ultrastructure were investigated and correlated to changes in renal gamma-glutamyl transpeptidase (gamma-GTPase) activity, mercury (Hg) accumulation, and renal function (serum creatinine and urea nitrogen). Three experimental protocols were used to investigate CH3Hg and Se interactions of both Se-sufficient and Se-deficient mice involving ip injection of the following administered alone or in combination: CH3Hg (4.0 mg/kg) and Se (0.16 mg/kg) daily for 7 days, CH3Hg (1.0 mg/kg) and Se (0.08 mg/kg) daily for 20 days, and a single acute dose of CH3Hg (8.0 mg/kg). Acivicin (12 to 50 mg/kg), an antitumor glutamine antagonist, was also used as a highly effective specific inhibitor of the gamma-GTPase. Our results show that CH3Hg administered to Se-deficient mice for 7 or 20 days resulted in significant (p less than or equal to 0.05) but only moderate inhibition (20%) of gamma-GTPase activity and extensive renal ultrastructural damage. Acivicin-treated mice had significant inhibition of gamma-GTPase activity (80%) following a single injection while ultrastructural damage was substantial only after several days of administration. These results may indicate different modes of action of acivicin and CH3Hg. Acivicin inhibited gamma-GTPase prior to renal damage while CH3Hg produced greater pathological effects with only moderate gamma-GTPase inhibition. Renal damage from acute and chronic CH3Hg toxicity occurred after distinct neurological signs were present. Selenium administered to Se-deficient mice ameliorated both the neurotoxic effects and nephrotoxic action of CH3Hg. While Se and CH3Hg treatments caused some of the same ultrastructural pathology as the treatment with CH3Hg alone (cytoplasmic vacuolation, increased lysosomal profile, mitochondrial swelling, and extrusion of cellular masses into the tubular lumen), degeneration was not as extensive. Although the total doses administered during both the 7- and the 20-day studies were similar, mice from the chronic 20-day study showed greater ultrastructural pathological effects from CH3Hg. The primary effects of CH3Hg appeared to be on the lysosomal system, while acivicin exerted its effects on the mitochondrial and endoplasmic reticulum systems. The accumulation studies on Hg suggest that dietary Se may have only an initial protective effect against Hg accumulation in the kidney while injected Se offers longer protection.(ABSTRACT TRUNCATED AT 400 WORDS)
Fair
P H
PH
Dougherty
W J
WJ
Braddon
S A
SA
D000818:Animals; D003404:Creatinine / Q000097:blood; D004347:Drug Interactions; D005260:Female; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D007684:Kidney Tubules / Q000648:ultrastructure; D008628:Mercury / Q000378:metabolism; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D012643:Selenium / Q000494:pharmacology*; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors*
D007555:Isoxazoles; D008767:Methylmercury Compounds; D003404:Creatinine; D005723:gamma-Glutamyltransferase; D008628:Mercury; D012643:Selenium; C006303:acivicin