Age‐ and Sex‐Dependent Dichlorovinyl Cysteine (DCVC) Accumulation and Toxicity in the Mouse Kidney: Relation to Development of Organic Anion Transport and β‐Lyase Activity

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Abstract
The age‐ and sex‐dependent changes in mouse kidney accumulation and toxicity ofS‐1,2‐dichlorovinyl cysteine (DCVC) was investigated. The results were compared to developmental changes in the basal activities of organic anion transportin vitro(PAH uptake) and of cysteine conjugate β‐lyase (substrate: benzothiazolyl cysteine). Following14C‐DCVC (5 mg/kg body wt. orally), the renal14C‐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 kidney14C‐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 β‐lyase activities did not directly mirror the age‐dependent increase in kidney radioactivity. Sex differences in anion transport and β‐lyase activities were also seen, the former activity being highest in the male mouse and the latter in the female. The conflicting results of14C‐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 increased14C‐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 β‐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.