AGE-DEPENDENT AND SEX-DEPENDENT DICHLOROVINYL CYSTEINE (DCVC) ACCUMULATION AND TOXICITY IN THE MOUSE KIDNEY - RELATION TO DEVELOPMENT OF ORGANIC ANION TRANSPORT AND BETA-LYASE ACTIVITY

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 C-14-DCVC (5 mg/kg body wt. orally), the renal C-14-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 C-14-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 C-14-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 C-14-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.