Age- and sex-dependent dichlorovinyl cysteine (DCVC) accumulation and toxicity in the mouse kidney: relation to development of organic anion transport and beta-lyase activity

Abstract

The age- and sex-dependent changes in mouse kidney accumulation and toxicity of S-1,2-dichlorovinyl cysteine (DCVC) was investigated. The results were compared to developmental changes in the basal activities of organic anion transport in vitro (PAH uptake) and of cysteine conjugate beta-lyase (substrate: benzothiazolyl cysteine). Following 14C-DCVC (5 mg/kg body wt. orally), the renal 14C-accumulation increased with age, whereas the degree of tubular DCVC lesions was about the same at all time points. Regarding the sex differentiation in adult mice, both the kidney 14C-accumulation levels and the kidney lesion (5 mg/kg DCVC) were most accentuated in the female mouse. However, at a higher dose (25 mg/kg), the male kidney was most affected. Changes in the anion transport and beta-lyase activities did not directly mirror the age-dependent increase in kidney radioactivity. Sex differences in anion transport and beta-lyase activities were also seen, the former activity being highest in the male mouse and the latter in the female. The conflicting results of 14C-accumulation and histopathology in developing mice, may be explained by the ongoing development of the kidney; increase in the number of functionally active nephrons may result in an increased 14C-accumulation (in d.p.m./mg wet wt.) but still the same degree of lesion, when estimated per nephron. In the adult mice, the higher susceptibility of the female may be correlated to the higher beta-lyase activity in the same sex. Regarding the inversed results at a higher dose, rate limitations of transport and bioactivation systems may play a role.