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吉非贝齐和氯贝酸对大鼠肝细胞过氧化物酶体酶及胆固醇合成影响的比较。

Comparison of the effects of gemfibrozil and clofibric acid on peroxisomal enzymes and cholesterol synthesis of rat hepatocytes.

作者信息

Hashimoto F, Taira S, Hayashi H

机构信息

Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan.

出版信息

Biol Pharm Bull. 1998 Nov;21(11):1142-7. doi: 10.1248/bpb.21.1142.

DOI:10.1248/bpb.21.1142
PMID:9853402
Abstract

We studied whether the peroxisomal proliferation, induction of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) and activation of cholesterol synthesis by gemfibrozil shown in whole body (Hashimoto F., Ishikawa T., Hamada S. and Hayashi H., Biochemical. Pharm., 49, 1213-1221 (1995)) is also detected at a culture cell level, and we made a comparative analysis of the effects of clofibric acid. Gemfibrozil at 0.25 mM increased the activity of some peroxisomal enzymes (catalase and the cyanide-insensitive fatty acyl-CoA oxidizing system) after incubation for 72 h. However, contrary to whole body experiments, gemfibrozil decreased the activity of HMG-CoA reductase and cholesterol synthesis from [14C]acetate. At 1 mM, gemfibrozil decreased not only the activity of HMG-CoA reductase and cholesterol synthesis, but also the protein content of the cells and peroxisomal enzyme activity, indicating nonspecific inhibition at this concentration. Clofibric acid (0.25 and 1 mM) increased the activity of peroxisomal enzymes, but decreased the activity of HMG-CoA reductase and cholesterol synthesis. With respect to the direct effect on HMG-CoA reductase in the cell homogenate, gemfibrozil at 0.25 mm did not affect the activity, but it clearly inhibited the activity at 2 mM and above. Clofibric acid at 2 mM hardly affected the activity, but it clearly decreased the activity at 5 mM and over. That is, gemfibrozil directly inhibited the activity more strongly than clofibric acid. The direct inhibition of the enzyme itself required higher concentrations of both agents than did inhibition at the culture cell level. These results suggest that the cytotoxicity of gemfibrozil is greater than that of clofibric acid, and that gemfibrozil, as well as clofibric acid, can induce peroxisomal enzymes in the culture cell level. In contrast to whole body results, gemfibrozil may suppress cholesterol synthesis from [14C]acetate through the inhibition of HMG-CoA reductase at the culture cell level. The decreases in the reductase activity caused by gemfibrozil and clofibric acid at the culture cell level may not be caused by the direct inhibition of the enzyme.

摘要

我们研究了在全身实验中观察到的吉非贝齐诱导的过氧化物酶体增殖、3-羟基-3-甲基戊二酰辅酶A还原酶(HMG-CoA还原酶)的诱导以及胆固醇合成的激活(Hashimoto F.、Ishikawa T.、Hamada S.和Hayashi H.,《生化药理学》,49,1213 - 1221(1995))在培养细胞水平上是否也能检测到,并且我们对氯贝酸的作用进行了比较分析。0.25 mM的吉非贝齐孵育72小时后增加了一些过氧化物酶体酶(过氧化氢酶和对氰化物不敏感的脂肪酰辅酶A氧化系统)的活性。然而,与全身实验相反,吉非贝齐降低了HMG-CoA还原酶的活性以及[14C]乙酸盐合成胆固醇的能力。在1 mM时,吉非贝齐不仅降低了HMG-CoA还原酶的活性和胆固醇合成,还降低了细胞的蛋白质含量和过氧化物酶体酶活性,表明在此浓度下存在非特异性抑制。氯贝酸(0.25和1 mM)增加了过氧化物酶体酶的活性,但降低了HMG-CoA还原酶的活性和胆固醇合成。关于对细胞匀浆中HMG-CoA还原酶的直接作用,0.25 mM的吉非贝齐不影响其活性,但在2 mM及以上时明显抑制其活性。2 mM的氯贝酸对其活性影响不大,但在5 mM及以上时明显降低其活性。也就是说,吉非贝齐比氯贝酸更强烈地直接抑制该酶的活性。与对酶本身的直接抑制相比,两种药物在培养细胞水平上产生抑制作用所需的浓度更高。这些结果表明,吉非贝齐的细胞毒性大于氯贝酸,并且吉非贝齐以及氯贝酸都能在培养细胞水平上诱导过氧化物酶体酶。与全身实验结果相反,在培养细胞水平上,吉非贝齐可能通过抑制HMG-CoA还原酶来抑制[14C]乙酸盐合成胆固醇。吉非贝齐和氯贝酸在培养细胞水平上导致的还原酶活性降低可能不是由对该酶的直接抑制引起的。

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