Wagner M, Toews A D, Morell P
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill 27599-7250, USA.
J Neurochem. 1995 May;64(5):2169-76. doi: 10.1046/j.1471-4159.1995.64052169.x.
A peripheral neuropathy characterized by a transient demyelinating/remyelinating sequence results when young rats are fed a tellurium-containing diet. The neuropathy occurs secondary to a systemic block in cholesterol synthesis. Squalene accumulation suggested the lesion was at the level of squalene expoxidase, a microsomal monooxygenase that uses NADPH cytochrome P450 reductase to receive its necessary reducing equivalents from NADPH. We have now demonstrated directly specificity for squalene epoxidase; our in vitro studies show that squalene epoxidase is inhibited 50% in the presence of 5 microM tellurite, the presumptive in vivo active metabolite. Under these conditions, the activities of other monooxygenases, aniline hydroxylase and benzo(a)pyrene hydroxylase, were inhibited less than 5%. We also present data suggesting that tellurite inhibits squalene epoxidation by interacting with highly susceptible -SH groups present on this monooxygenase. In vivo studies of specificity were based on the compensatory response to feeding of tellurium. Following tellurium intoxication, there was up-regulation of squalene epoxidase activity both in liver (11-fold) and sciatic nerve (fivefold). This induction was a specific response, as demonstrated in liver by the lack of up-regulation following exposure to the nonspecific microsomal enzyme inducer, phenobarbital. As a control, we also measured the microsomal monooxygenase activities of aniline hydroxylase and benzo(a)pyrene hydroxylase. Although they were induced following phenobarbital exposure, activities of these monooxygenases were not affected following tellurium intoxication, providing further evidence of specificity of tellurium intoxication for squalene epoxidase.
当给幼鼠喂食含碲饮食时，会引发一种以短暂性脱髓鞘/再髓鞘化序列为特征的周围神经病变。这种神经病变继发于胆固醇合成的系统性阻断。角鲨烯积累表明病变发生在角鲨烯环氧酶水平，角鲨烯环氧酶是一种微粒体单加氧酶，它利用NADPH细胞色素P450还原酶从NADPH获取所需的还原当量。我们现已直接证明了对角鲨烯环氧酶的特异性；我们的体外研究表明，在5 microM亚碲酸盐（推测的体内活性代谢物）存在的情况下，角鲨烯环氧酶被抑制了50%。在这些条件下，其他单加氧酶、苯胺羟化酶和苯并(a)芘羟化酶的活性被抑制不到5%。我们还提供数据表明，亚碲酸盐通过与这种单加氧酶上存在的高度敏感的 -SH基团相互作用来抑制角鲨烯环氧化。特异性的体内研究基于对碲喂养的代偿反应。碲中毒后，肝脏（11倍）和坐骨神经（5倍）中的角鲨烯环氧酶活性均上调。这种诱导是一种特异性反应，如在肝脏中所证明的，暴露于非特异性微粒体酶诱导剂苯巴比妥后未出现上调。作为对照，我们还测量了苯胺羟化酶和苯并(a)芘羟化酶的微粒体单加氧酶活性。虽然它们在苯巴比妥暴露后被诱导，但这些单加氧酶的活性在碲中毒后并未受到影响，这进一步证明了碲中毒对角鲨烯环氧酶的特异性。
