Contribution to the mechanism of chromate nephrotoxicity in developing rats: EPR investigations.
The effect of 2 mg and 1 mg Na2Cr2O7 (Cr)/100 g body wt. on renal function was investigated in 10- and 55-day-old rats, respectively. These doses were followed by equal Cr concentrations in the renal tissue of both age groups. Confirming previous data we found lower nephrotoxicity in young than in adult rats. The concentration of glutathione (GSH) and the activity of glutathione reductase (GSSG reductase) in renal tissue of adult rats were diminished by buthionine sulfoximine (BSO) and lomustine (CCNU) administration, respectively. In these animals Cr nephrotoxicity was decreased significantly. Lower nephrotoxicity was accompanied by slower disappearance of Cr(VI) from renal tissue homogenate in vitro. The time course of Cr(VI) reduction demonstrated by the signal intensity of Cr(V), as recorded by electron spin resonance (EPR) spectroscopy in the supernatant of renal tissue homogenate, enabled us to follow the reduction of Cr(VI) to Cr(III) via Cr(V). Maximally reached Cr(V) concentrations lowest in young rats, did not differ significantly in adult control and BSO and BSO + CCNU treated rats. Further reduction of Cr(V) to Cr(III) which appeared most rapidly in adult rats, was delayed by pretreatment with BSO and CCNU. From our results we concluded that (1) reduction of Cr(VI) was more related to the concentration of GSH than to the activity of GSSG reductase, (2) the formation of Cr-GSH-complexes with GSH oxidation seemed to be the first step of Cr(VI) metabolism, and (3) the stabilization of reactive Cr(V) by GSH seemed to be decisive for the preventive effect of BSO and CCNU as well as for age differences in chromate nephrotoxicity.
Appenroth
D
D
Institute of Pharmacology and Toxicology, Friedrich-Schiller University, Jena, Germany.
Rost
M
M
Friedrich
M
M
Schulz
O
O
D000367:Age Factors; D000818:Animals; D000833:Animals, Suckling; D002478:Cells, Cultured; D002840:Chromates / Q000378:metabolism / Q000633:toxicity*; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced*; D008297:Male; D008956:Models, Chemical; D051381:Rats; D017670:Sodium Compounds / Q000378:metabolism / Q000633:toxicity*
D002840:Chromates; D017670:Sodium Compounds; C028982:sodium chromate(VI); D005978:Glutathione