THE ROLE OF THE BENOMYL METABOLITE CARBENDAZIM IN BENOMYL-INDUCED TESTICULAR TOXICITY

The present study has investigated the role of benomyl (BNL) vs carben dazim (CBZ) in BNL-induced testicular toxicity. Equivalent molar conce ntrations of BNL and CBZ were administered to rats intraperitoneally ( 859 mu mol/kg) or by direct injection into the testis (1.37 mu mol/tes tis). Whereas no significant testicular damage was observed both 1 and 2 hr after BNL administration by the ip route, CBZ administration res ulted in sloughing of the seminiferous epithelium after 1 hr, which in creased 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 epitheli um. Testicular levels of CBZ and BM, were measured at various times af ter both routes of administration. The AUC from the concentration of C BZ 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 co ntribution 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 mu M and that for B NL was 75 mu M. 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 inh ibitor of testicular microtubule assembly. (C) 1997 Academic Press.