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 func tion 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 nephrotoxicit y in young than in adult rats. The concentration of glutathione (GSH) and the activity of glutathione reductase (GSSG reductase) in renal ti ssue of adult rats were diminished by buthionine sulfoximine (BSO) and lomustine (CCNU) administration, respectively. In these animals Cr ne phrotoxicity was decreased significantly. Lower nephrotoxicity was acc ompanied by slower disappearance of Cr(VI) from renal tissue homogenat e in vitro. The time course of Cr(VI) reduction demonstrated by the si gnal intensity of Cr(V), as recorded by electron spill resonance (EPR) spectroscopy in the supernatant of renal tissue homogenate, enabled u s to follow the reduction of Cr(VI) to Cr(III) via Cr(V). Maximally re ached Cr(V) concentrations, lowest in young rats, did not differ signi ficantly in adult control and BSO and BSO + CCNU treated rats. Further reduction of Cr(V) to Cr(III) which appeared most rapidly in adult ra ts, was delayed by pretreatment with BSO and CCNU. From our results we concluded that (1) reduction of Cr(VI) was more related to the concen tration of GSH than to the activity of GSSG reductase, (2) the formati on of Cr-GSH-complexes without GSH oxidation seemed to be the first st ep of Cr(VI) metabolism, and (3) the stabilization of reactive Cr(V) b y GSH seemed to be decisive for the preventive effect of BSO and CCNU as well as for age differences in chromate nephrotoxicity.