Possible role of glutathione in chromium(VI) metabolism and toxicity in rats.
The effect of Cr(VI) on liver, kidney, and lung glutathione (GSH) levels and the effect of GSH depletion on Cr(VI)-induced nephrotoxicity were studied in male Sprague-Dawley rats (150-200 g). GSH levels, measured as nonprotein sulfhydryls, were determined between 0.5 and 26 hr after intraperitoneal injection of the maximum non-toxic dose of sodium dichromate (10 mg/kg). While Cr(VI) at this dose did not significantly change hepatic, renal, or pulmonary GSH levels, there appeared to be an initial decrease of hepatic GSH followed by an increase to approximately 120% of control between 5 and 12.5 hr after Cr(VI) treatment. The increase in hepatic GSH levels was significant 5 hr after treatment with 20 mg/kg sodium dichromate, was manifested as an increase in both non-protein sulfhydryls and total glutathione, and was prevented by L-buthionine sulfoximine (BSO) pretreatment. In rats pretreated with 4.0 mmol/kg BSO to deplete GSH, subsequent treatment with Cr(VI) further reduced hepatic GSH levels 2 hr after Cr(VI) treatment and inhibited weight gain in the first 24 hr after treatment. Intraperitoneal injection of Cr(VI) did not inhibit hepatic glutathione reductase activity, even at toxic doses. Depletion of renal GSH to approximately 25% of control with BSO potentiated the acute nephrotoxicity of 30 mg/kg sodium dichromate as measured by serum urea nitrogen levels and relative kidney weight. However, GSH depletion with BSO did not appear to affect the incidence of glucosuria, haematuria, or lysozymuria over a range of Cr(VI) doses, nor did it affect renal uptake of Cr. Taken together, these data show that GSH protects against the acute nephrotoxicity of Cr(VI), although it is not clear whether GSH is directly involved in the intracellular metabolism of Cr(VI) at non-toxic doses.
Standeven
A M
AM
Department of Pharmacology & Toxicology, Dartmouth Medical School, Hanover, NH 03755.
Wetterhahn
K E
KE
D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D019328:Buthionine Sulfoximine; D002840:Chromates / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity; D005978:Glutathione / Q000302:isolation & purification / Q000502:physiology*; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains
D000963:Antimetabolites; D002840:Chromates; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C016104:sodium bichromate; D005978:Glutathione