A comparison of the effects of intraperitoneal and subcutaneous routes of administration of sodium dichromate on nephrotoxicity in rats was studied. Dichromate when injected subcutaneously (SC group) produced a higher degree of nephrotoxicity than when administered intraperitoneally (IP group). It caused severe progressive proteinuria followed by polyuria and glucosuria, reaching maximum levels at 3 days after treatment in the SC group, whereas it produced mild proteinuria without glucosuria in the IP group. The dose-dependent increases in blood urea nitrogen (BUN) and creatinine concentrations, shown in the SC group, were not observed in the IP group. However, between the two groups, there were no great differences in either the urinary excretion rate of chromium or the electrophoretic patterns of urinary protein in the day 1 urine specimens. Pretreatment of phenobarbital (PB) had no remarkable effect on the dichromate-induced nephrotoxicity. In contrast, it potentiated dichromate-induced hepatotoxicity, the indices of which were the elevation in serum alanine aminotransferase (ALT) activity and hepatic lipid peroxide formation. These results suggest that the dependence of dichromate-induced nephrotoxicity on the route of administration is related to the chemical forms of chromium reaching the kidney, and the necrotizing property of dichromate results from its metabolic fate in vivo.

Ascorbate treatment 30 min prior to sodium dichromate (20 or 30 mg/kg, s.c.) shows higher potency than that of glutathione (GSH) in protecting against both the metabolic disturbance and nephrotoxicity induced by dichromate. However, ascorbate treatment after 2 h of dichromate intoxication had no effect on dichromate-induced blood urea nitrogen (BUN) elevation 3 days after intoxication. In contrast, dichromate-induced glucosuria, which reached maximum levels at 3 days after treatment, was significantly decreased by GSH or N-acetyl cysteine (NAC) treatment, even if its administration was after 24 h of dichromate intoxication. Pretreatment with GSH depletors such as diethyl maleate (DEM) and buthionine sulfoximine (BSO) had no effect on dichromate-induced nephrotoxicity. GSH levels in the liver and kidney were not affected at 3 h after dichromate treatment. However, dichromate significantly increased tissue GSH levels with a marked increase in liver per kidney GSH ratio at 24 h after treatment, if food was withheld subsequent to dichromate treatment, indicating that GSH biosynthesis resulted from the accelerated protein breakdown. These results suggest that GSH-mediated dichromate reduction is not a kinetically favorable pathway in vivo; however, GSH plays an important role in protection against dichromate-induced nephrotoxicity. In addition, the cellular metabolism of dichromate in the early period after treatment is important in the pathogenesis of its nephrotoxicity.

The effect of sodium dichromate on cellular metabolism was investigated. Intraperitoneal injection of sodium dichromate into the rat (20 or 40 mg/kg) caused significant increases in serum lactate, pyruvate, and creatinine concentrations within 15 min after intoxication. Severe hyperglycemia occurred thereafter, as a result of increased hepatic glycogenolysis, which was seen in the first 2 h after dichromate. However, liver glycogen was resynthesized in 24 h-fasted rats after glucose refeeding. Dichromate decreased serum total amino acids, with a consequent increase in blood urea nitrogen (BUN) concentration. Unlike HgCl2 (2 mg/kg, i.p.), As2O3 (5 mg/kg, i.p.), and KCN (5 mg/kg, i.p.), dichromate showed the largest metabolic disturbance only in the early period after treatment. In addition, dichromate produced cyanosis, which appeared during the period of the accelerated glycolysis and breakdown of creatinine phosphate. Regardless of chemical species, only the hexavalent chromium compounds had an effect on the cellular metabolism. Trivalent chromium compounds had no effect at all. These results suggest that dichromate possesses a characteristic dual action on cellular metabolism, which might be related to its metabolic fate.