Cho S Y, Kim J H, Paik Y K
Department of Biochemistry, Yonsei University, Seoul, Korea.
Mol Cells. 1998 Apr 30;8(2):233-9.
The fact that administration of tamoxifen (Tam) to humans and laboratory animals (e.g., rats and monkeys) results in both a drastic reduction in cholesterol and a marked accumulation of certain sterol intermediates in their serum led us to undertake more direct biochemical studies on the mechanism of Tam's inhibitory action on the cholesterogenic enzymes. Of the five rat hepatic lanosterol-converting enzymes examined, the enzyme most sensitive to inhibition by Tam was sterol delta 8-isomerase (delta 8-SI) (a 208-fold inhibition relative to lanosterol 14 alpha-methyl demethylase), followed by sterol delta 24-reductase (13-fold) and sterol delta 14-reductase (5.2-fold). The inhibition patterns of all four affected enzymes were found to be noncompetitive, despite widely different inhibition constants (Ki) of 0.21 to 23.5 microM. The inhibitory activity of Tam on delta 8-SI was not affected by detergent-mediated solubilization of the microsomes. In Chinese hamster ovary cells, inhibition of delta 8-SI activity (IC50 = 0.15 microM) was paralleled by a decreased rate of [14C]-mevalonate incorporation into cholesterol (IC50 = 0.70 microM). Our results should provide more insight into an underlying mechanism of Tam's cardioprotective role by interfering the operation of the pathway of cholesterol biosynthesis from lanosterol in mammals.
给人类和实验动物（如大鼠和猴子）服用他莫昔芬（Tam）会导致其血清中胆固醇急剧降低以及某些甾醇中间体显著积累，这一事实促使我们对Tam对胆固醇生成酶的抑制作用机制进行更直接的生化研究。在所检测的五种大鼠肝脏羊毛甾醇转化酶中，对Tam抑制最敏感的酶是甾醇δ8-异构酶（δ8-SI）（相对于羊毛甾醇14α-甲基脱甲基酶有208倍的抑制作用），其次是甾醇δ24-还原酶（13倍）和甾醇δ14-还原酶（5.2倍）。尽管四种受影响酶的抑制常数（Ki）差异很大，在0.21至23.5微摩尔之间，但发现它们的抑制模式均为非竞争性。Tam对δ8-SI的抑制活性不受去污剂介导的微粒体溶解的影响。在中国仓鼠卵巢细胞中，δ8-SI活性的抑制（IC50 = 0.15微摩尔）与[14C]-甲羟戊酸掺入胆固醇的速率降低（IC50 = 0.70微摩尔）平行。我们的结果应能更深入地了解Tam通过干扰哺乳动物中从羊毛甾醇合成胆固醇途径的运作而发挥心脏保护作用的潜在机制。
