TELLURITE SPECIFICALLY AFFECTS SQUALENE EPOXIDASE - INVESTIGATIONS EXAMINING THE MECHANISM OF TELLURIUM-INDUCED NEUROPATHY

A peripheral neuropathy characterized by a transient demyelinating/rem yelinating sequence results when young rats are fed a tellurium-contai ning diet. The neuropathy occurs secondary to a systemic block in chol esterol synthesis. Squalene accumulation suggested the lesion was at t he level of squalene epoxidase, a microsomal monooxygenase that uses N ADPH cytochrome P450 reductase to receive its necessary reducing equiv alents from NADPH, We have now demonstrated directly specificity for s qualene epoxidase; our in vitro studies show that squalene epoxidase i s inhibited 50% in the presence of 5 mu M tellurite, the presumptive i n vivo active metabolite. Under these conditions, the activities of ot her monooxygenases, aniline hydroxylase and benzo(a)pyrene hydroxylase , were inhibited less than 5%, We also present data suggesting that te llurite inhibits squalene epoxidation by interacting with highly susce ptible -SH groups present on this monooxygenase. In vivo studies of sp ecificity were based on the compensatory response to feeding of tellur ium. Following tellurium intoxication, there was up-regulation of squa lene epoxidase activity both in liver (11-fold) and sciatic nerve (fiv efold). This induction was a specific response, as demonstrated in liv er by the lack of up-regulation following exposure to the nonspecific microsomal enzyme inducer, phenobarbital, As a control, we also measur ed the microsomal monooxygenase activities of aniline hydroxylase and benzo(a)pyrene hydroxylase. Although they were induced following pheno barbital exposure, activities of these monooxygenases were not affecte d following tellurium intoxication, providing further evidence of spec ificity of tellurium intoxication for squalene epoxidase.