Differential metabolism of fenvalerate and granuloma formation. II. Toxicological significance of a lipophilic conjugate from fenvalerate.

Male mice of the ddY strain were fed a diet containing the [2S, alpha S]-, [2S, alpha RS]-, [2R, alpha S]-, and [2R, alpha R]-isomers of fenvalerate. Microgranulomatous changes were observed only in mice treated with the [2R, alpha S]-isomer at 125 and 1000 ppm for 1, 2, or 3 months. In contrast, the changes did not occur in mice treated with the [2R, alpha R]-isomer under the same conditions. Feeding of the [2S, alpha S]- and [2S, alpha RS]-isomers for 1 year did not cause the microgranulomatous changes at 500 or 1000 ppm. To clarify the causative agent of granuloma formation, cholesterol ester of 2-(4-chlorophenyl)isovaleric acid (CPIA), a lipophilic conjugate from the [2R, alpha S]-isomer of fenvalerate, was injected iv into ddY mice. Microgranulomatous changes were observed in the liver of mice treated with the [2R]-, [2S]-, or [2RS]-CPIA-cholesterol ester 1 week after a single treatment of 1, 10, or 100 mg/kg, as well as in liver of mice treated with a single dose of 10 or 30 mg/kg of the [2R]-CPIA-cholesterol ester and kept up to 26 weeks afterward. Histochemistry and microscopic autoradiography of the liver of mice demonstrated the presence of tritium derived from 3H-labeled[2R]-2-(4-chlorophenyl)isovalerate and cholesterol. Histochemistry also was positive for cholesterol ester in livers of mice treated with the [2R, alpha S]-isomer of fenvalerate. These results lend support for the hypothesis that CPIA-cholesterol ester is the causative agent of microgranulomatous changes induced by fenvalerate.