BIS (2, 3-dibromopropyl) phosphate nephrotoxicity: Effect of sex and CoCl₂ pretreatment

Bis (2, 3-dibromopropyl) phosphate (BIS-BP) is one of two identified metabolites of Tris (2, 3-dibromopropyl) phosphate (TRIS-BP). We have previously shown that BIS-BP is more acutely nephrotoxic than TRIS-BP. We now report the effect of sex and inhibition of drug metabolism on BIS-BP toxicity. Compared to male rats, age-matched female rats developed less severe and extensive structural damage after BIS-BP. Renal dysfunction, as indexed by serum creatinine and in vitro renal cortical uptake of para-aminohippurate and N-(¹⁴C) methylnicotinamide was similar in males and females. Pretreatment of males with the drug metabolism inhibitor, cobaltous chloride, reduced both functional and structural evidence of BIS-BP toxicity. In separate studies, there was no difference in the distribution of radiolabel in male and female rats three days after administration of ¹⁴C-TRIS-BP. These studies showing that female rats are resistant to acute BIS-BP structural damage may explain the previously reported lack of carcinogenicity of TRIS-BP in female rats. The reduction of BIS-BP toxicity by CoCl₂ suggests that unidentified, nephrotoxic metabolites exist and are responsible for part of the nephrotoxicity of BIS-BP.