The role of the benomyl metabolite carbendazim in benomyl-induced testicular toxicity.
The present study has investigated the role of benomyl (BNL) vs carbendazim (CBZ) in BNL-induced testicular toxicity. Equivalent molar concentrations of BNL and CBZ were administered to rats intraperitoneally (859 mumol/kg) or by direct injection into the testis (1.37 mumol/testis). Whereas no significant testicular damage was observed both 1 and 2 hr after BNL administration by the ip route, CBZ administration resulted in sloughing of the seminiferous epithelium after 1 hr, which increased in severity at the 2-hr time point. Intratesticular treatment of BNL caused little testicular damage after 1 hr whereas an equimolar amount of CBZ elicited severe disruption of the seminiferous epithelium. Testicular levels of CBZ and BNL were measured at various times after both routes of administration. The AUC from the concentration of CBZ in the testis vs time plot showed an excellent relationship to the number of tubules which exhibited slouging. The BNL AUC also showed a straight-line relationship to severity of lesion. However, when the contribution of CBZ to the BNL response was subtracted, no effect of BNL was discernible. The effect of BNL and CBZ on testicular microtubule assembly was then investigated. IC50 for CBZ was 5 microM and that for BNL was 75 microM. Again, the effect of BNL on microtubule assembly could be largely accounted for by the presence of the CBZ breakdown product. These results strongly suggest that the BNL metabolite CBZ, and not BNL itself, is the mediator of BNL-induced testicular toxicity and inhibitor of testicular microtubule assembly.
Lim
J
J
Department of Environmental Toxicology, University of California, Davis 95616, USA.
Miller
M G
MG
D000818:Animals; D001542:Benomyl / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002219:Carbamates; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D008297:Male; D008854:Microscopy, Electron; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012671:Seminiferous Tubules / Q000187:drug effects / Q000473:pathology; D013737:Testis / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
D001562:Benzimidazoles; D002219:Carbamates; D005659:Fungicides, Industrial; D014404:Tubulin; C006698:carbendazim; D001542:Benomyl