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.
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D002788:Cholesterol Esters / Q000378:metabolism*; D006099:Granuloma / Q000139:chemically induced* / Q000473:pathology; D007306:Insecticides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008107:Liver Diseases / Q000473:pathology; D008198:Lymph Nodes / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D009570:Nitriles; D011722:Pyrethrins / Q000378:metabolism / Q000633:toxicity*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002788:Cholesterol Esters; D007306:Insecticides; D009570:Nitriles; D011722:Pyrethrins; C017690:fenvalerate