Mechanism of Sex-Related Differences in Nephrotoxicity of 1,2-Dichloropropane in Rats

Abstract

The contribution of testosterone to the nephrotoxic effects of 1,2-dichloropropane (DCP) was assessed by a series of castration and sex hormone replacement experiments on Wistar rats. The nephrotoxic action of DCP was evaluated by measuring the accumulation of organic anion and release of aspartate aminotransferase into the incubation medium using a renal cortical slice model. Our data show that sex, castration, and testosterone pretreatment are factors that influence the effect of DCP on renal cortical slices of rats Males appear to be more sensitive to nephrotoxic effects of DCP than females, male castration prevents the nephrotoxic effects of DCP, and pretreatment of females and castrated males with testosterone increases the susceptibility to DCP. In this study an attempt was made to evaluate the role of sex differences in the expression of enzymes participating in Phase I and Phase II detoxication reactions in order to explain the differences in sensitivity of the two genders to the nephrotoxic action of DCP. Our results implicate gender-specific expression of cytochrome P-450 in the kidneys as a predominant factor that determines the different susceptibilities of male and female rats to the nephrotoxic effect of DCP. We propose that the oxidation of DCP by CYP IIE1 is the first saturable and limiting step in the metabolic activation of DCP to nephrotoxic metabolites. It appears that, despite the fact that the nephrotoxic effect of DCP is determined mainly by its cysteine-conjugated metabolites, gluthathione (GSH) content and glutathione S-transferase (GST) activity in kidney are not directly related to increased androgen-related susceptibility to DCP.(ABSTRACT TRUNCATED AT 250 WORDS)

Superoxide dismutase and cytochrome P450 isoenzymes might be associated with higher risk of renal cell carcinoma in male patients

“…While castration of males is protective, testosteron treatment of females increased their susceptibility toward renal damage. The authors attributed this to different expression of cytochrome P450s, particularly CYP2E1 [32]. The mRNA expression for CYP2D6 was decreased in tumor tissue in a non gender-related manner.…”

Sex-related differences in renal toxicodynamics in rodents

“…In vitro, renal cortical slices prepared from male Wistar rat kidney were more sensitive to DCP effects than those from females [110]. Further, in a classic sex hormone paradigm study, Odinecs et al [111] confirmed that male rats are more sensitive than females and that testosterone plays a pivotal role in nephrotoxicity.…”