metallothionein and acivicin

To determine whether Hg accumulated in renal cells is secreted into the lumen of proximal tubules with intracellular glutathione (GSH) and reabsorbed by tubular cells via a gamma-glutamyltranspeptidase (gamma-GTP)-dependent process as in the case of GSH itself, the effect of postadministration of acivicin (1 mmol/kg i.p.), a gamma-GTP inhibitor, on renal Hg accumulation was investigated in mice. Renal Hg content 4 hr after injection of CH3HgCl or HgCl2 (5 mumol/kg i.v.) was decreased to 35 or 44% of control, respectively, but urinary Hg excretion was increased by acivicin administration 2 hr after injection of the mercurials. When renal GSH was decreased to 19% of control by treatment with DL-buthionine-S,R-sulfoximine (4 mmol/kg s.c.) 2 hr before acivicin injection, the increase in urinary Hg excretion caused by acivicin was suppressed. Acivicin administration 24 hr after injection of the mercurials decreased renal methylmercury content determined 2 hr after acivicin injection and increased urinary Hg excretion. The postadministration of acivicin, however, did not affect the renal content of inorganic Hg which predominantly bound to metallothionein (MT) induced by HgCl2 itself. Pretreatment with Bi(NO3)3 as a renal MT inducer diminished the effect of acivicin administered 2 hr after HgCl2 injection on renal Hg content and urinary excretion. These results suggest that methylmercury and inorganic Hg bound to ligands other than MT in renal cytosol may be secreted into the lumen of proximal tubules with intracellular GSH and be reabsorbed via a gamma-GTP-dependent process.

Topics: Absorption; Animals; Bismuth; gamma-Glutamyltransferase; Glutathione; Isoxazoles; Kidney Tubules; Male; Mercury; Metallothionein; Mice; Mice, Inbred ICR; Nitrates

Eighteen hours of immobilization stress, accompanied by food and water deprivation, increased liver metallothionein (MT) but decreased kidney MT levels. Food and water deprivation alone had a significant effect only on liver MT levels. In contrast, stress and food and water deprivation increased both liver and kidney lipid peroxidation levels, indicating that the relationship between MT and lipid peroxidation levels (an index of free radical production) is unclear. Adrenalectomy increased both liver and kidney MT levels in basal conditions, whereas the administration of corticosterone in the drinking water completely reversed the effect of adrenalectomy, indicating an inhibitory role of glucocorticoids on MT regulation in both tissues. Changes in glutathione (GSH) metabolism produced significant effects on kidney MT levels. Thus, the administration of buthionine sulfoximine, an inhibitor of GSH synthesis, decreased kidney GSH and increased kidney MT content, suggesting that increased cysteine pools because of decreased GSH synthesis might increase kidney MT levels through an undetermined mechanism as it appears to be the case in the liver. However, attempts to increase kidney MT levels by the administration of cysteine or GSH were unsuccessful, in contrast to what is known for the liver. The present results suggest that there are similarities but also substantial differences between liver and kidney MT regulation in these experimental conditions.

Topics: Adrenal Glands; Adrenalectomy; Animals; Buthionine Sulfoximine; Corticosterone; Glutathione; Isoxazoles; Kidney; Liver; Male; Metallothionein; Methionine Sulfoximine; Organ Specificity; Rats; Rats, Sprague-Dawley; Restraint, Physical; Starvation; Stress, Physiological

Stress and starvation increased liver metallothionein (MT) and decreased liver glutathione (GSH) levels. Serum cysteine plus cystine levels were increased by stress. The exogenous administration of GSH, while not modifying hepatic GSH content, increased liver MT levels in basal and starved rats but not in stressed rats. Liver and serum cysteine levels were increased by GSH administration, a process partially reverted by the irreversible inhibitor of gamma-glutamyl transpeptidase, alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid. Mouse and rat liver MT levels were also increased by buthionine sulfoximine, an inhibitor of GSH synthesis, indicating that GSH is not a necessary precursor of MT. In addition, the hepatic MT content was increased by the administration of cysteine in a dose-response manner. These results suggest that hepatic MT synthesis is elevated by increased cysteine pools, and that MT, GSH and cysteine levels are somehow inter-related. MT, besides GSH, may be contemplated as a putative intracellular reservoir of cysteine in the liver of adult rats.

Topics: Animals; Body Weight; Buthionine Sulfoximine; Cysteine; Glutathione; Isoxazoles; Liver; Male; Metallothionein; Methionine Sulfoximine; Organ Size; Rats; Rats, Inbred Strains; Starvation; Stress, Physiological; Zinc