Xu G, Salen G, Lea M, Tint G S, Nguyen L B, Batta A K, Chen T S, Shefer S
Gastrointestinal Research Lab, VA Medical Center, East Orange, NJ 07018-1095, USA.
Hepatology. 1996 Aug;24(2):440-5. doi: 10.1002/hep.510240224.
The conversion of 7-dehydrocholesterol to cholesterol is the last reaction in the cholesterol biosynthesis pathway catalyzed by the microsomal enzyme, 7-dehydrocholesterol-delta 7-reductase. We studied whether malignant tumor growth that depends on cholesterol could be slowed by inhibiting late cholesterol biosynthesis. The inhibitor 7-dehydrocholester-delta 7-reductase, BM 15.766 alone, or in combination with 2% cholesterol was fed to 20 male Buffalo rats for 2 weeks immediately after Morris hepatoma 7288CTC was implanted in both flanks. Tumor weights were compared and sterol composition, hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase activity, and low-density lipoprotein (LDL) receptor binding in the tumor were correlated with those in the liver. In the plasma of rats treated with BM 15.766, cholesterol levels dropped 75% and the precursor, 7-dehydrocholesterol rose substantially. Tumor weights were 43% less (P < .05) than controls (5.9 +/- 1.5 g vs. 10.4 +/- 2.2 g) with sterol concentrations reduced 25%, and the precursor, 7-dehydrocholesterol, increased to represent 71% of the tumor sterols. Feeding cholesterol with BM 15.766 normalized plasma but only partially restored tumor cholesterol concentrations, which still remained 49% below the hepatomas in the control group. With BM 15.766, hepatic cholesterol decreased 76% and was associated with a marked rise of 7-dehydrocholesterol that could be almost entirely prevented by feeding cholesterol. After the tumor was implanted, hepatic HMG-CoA reductase activity increased 56% and was 8.6 times higher than in the tumor. Enzyme activities were enhanced about 50% in the liver and the tumor after BM 15.766 was administered but decreased 38% below control when cholesterol was added to the diet. Hepatic receptor-mediated LDL binding rose 67% after tumor implantation, and declined to control levels with cholesterol feeding. These results suggest that de novo cholesterol synthesis in Morris hepatoma 7288CTC is much lower than the liver and tumor growth depends on circulating plasma cholesterol. Inhibiting the last step in cholesterol biosynthesis profoundly reduced tissue and plasma cholesterol concentrations and accumulated precursors substantially to slow hepatoma growth. Feeding cholesterol restored liver but not hepatoma cholesterol levels. Thus, inhibiting late cholesterol synthesis hinders growth of rapidly enlarging malignant tumors.
7-脱氢胆固醇向胆固醇的转化是胆固醇生物合成途径中的最后一步反应，由微粒体酶7-脱氢胆固醇-δ7-还原酶催化。我们研究了通过抑制胆固醇生物合成后期步骤，是否可以减缓依赖胆固醇的恶性肿瘤生长。在双侧植入Morris肝癌7288CTC后，立即将抑制剂7-脱氢胆固醇-δ7-还原酶BM 15.766单独或与2%胆固醇联合喂给20只雄性布法罗大鼠，持续2周。比较肿瘤重量，并将肿瘤中的甾醇组成、肝脏羟甲基戊二酰辅酶A（HMG-CoA）还原酶活性和低密度脂蛋白（LDL）受体结合情况与肝脏中的进行关联分析。在用BM 15.766治疗的大鼠血浆中，胆固醇水平下降了75%，前体7-脱氢胆固醇大幅上升。肿瘤重量比对照组减少了43%（P <.05）（5.9±1.5 g对10.4±2.2 g），甾醇浓度降低了25%，前体7-脱氢胆固醇增加，占肿瘤甾醇的71%。将胆固醇与BM 15.766一起喂食可使血浆正常化，但仅部分恢复肿瘤胆固醇浓度，仍比对照组肝癌低49%。使用BM 15.766时，肝脏胆固醇下降了76%，并与7-脱氢胆固醇的显著升高相关，喂食胆固醇几乎可以完全阻止这种升高。肿瘤植入后，肝脏HMG-CoA还原酶活性增加了56%，比肿瘤中的高8.6倍。给予BM 15.766后，肝脏和肿瘤中的酶活性增强了约50%，但当饮食中添加胆固醇时，酶活性比对照组下降了38%。肿瘤植入后，肝脏受体介导的LDL结合增加了67%，喂食胆固醇后降至对照水平。这些结果表明，Morris肝癌7288CTC中的从头胆固醇合成远低于肝脏，肿瘤生长依赖于循环血浆胆固醇。抑制胆固醇生物合成的最后一步可显著降低组织和血浆胆固醇浓度，并大量积累前体物质，从而减缓肝癌生长。喂食胆固醇可恢复肝脏但不能恢复肝癌的胆固醇水平。因此，抑制胆固醇合成后期步骤可阻碍快速增大的恶性肿瘤生长。
