Conde K, Roy S, Freake H C, Newton R S, Fernandez M L
Department of Nutritional Sciences, University of Connecticut, Storrs 06269, USA.
Lipids. 1999 Dec;34(12):1327-32. doi: 10.1007/s11745-999-0485-2.
The effects of atorvastatin and simvastatin on hydroxy methylglutaryl (HMG)-CoA reductase activity and mRNA abundance were studied in guinea pigs randomized to three groups: untreated animals and those treated with 20 mg/kg of atorvastatin or simvastatin. Guinea pigs were fasted for 0, 6, 12, or 18 h in an attempt to remove the drug from their systems. Reductase activity and mRNA levels were analyzed after each time point. Reductase inhibitor treatment resulted in 50-62% lower cholesterol concentrations compared to untreated guinea pigs (P < 0.0001), while plasma triacylglycerol (TAG) concentrations did not differ among groups. Plasma cholesterol and TAG were 50-70% lower after 18 h fasting in the three groups (P < 0.001). In the nonfasting state, simvastatin and atorvastatin treatment did not affect HMG-CoA reductase activity compared with untreated animals. However, after 6 h of fasting, simvastatin-treated guinea pigs had higher HMG-CoA reductase activity than untreated animals (P < 0.01), suggesting that the drug had been removed from the enzyme. In contrast, atorvastatin-treated guinea pigs maintained low enzyme activity even after 18 h of fasting. Further, HMG-CoA reductase mRNA abundance was increased by sevenfold after atorvastatin treatment and by twofold after simvastatin treatment (P < 0.01). These results suggest that simvastatin and atorvastatin have different half-lives, which may affect HMG-CoA reductase mRNA levels. The increase in reductase activity by simvastatin during fasting could be related to an effect of this statin in stabilizing the enzyme. In contrast, atorvastatin, possibly due to its longer half-life, prolonged inhibition of HMG-CoA reductase activity and resulted in a greater increase in mRNA synthesis.
将豚鼠随机分为三组，研究阿托伐他汀和辛伐他汀对羟甲基戊二酰（HMG）-辅酶A还原酶活性和mRNA丰度的影响：未治疗的动物以及用20mg/kg阿托伐他汀或辛伐他汀治疗的动物。豚鼠禁食0、6、12或18小时，试图从其体内清除药物。在每个时间点后分析还原酶活性和mRNA水平。与未治疗的豚鼠相比，还原酶抑制剂治疗使胆固醇浓度降低了50-62%（P<0.0001），而各组间血浆三酰甘油（TAG）浓度无差异。三组在禁食18小时后血浆胆固醇和TAG降低了50-70%（P<0.001）。在非禁食状态下，与未治疗的动物相比，辛伐他汀和阿托伐他汀治疗不影响HMG-辅酶A还原酶活性。然而，禁食6小时后，辛伐他汀治疗的豚鼠的HMG-辅酶A还原酶活性高于未治疗的动物（P<0.01），表明药物已从酶中清除。相比之下，阿托伐他汀治疗的豚鼠即使在禁食18小时后仍保持低酶活性。此外，阿托伐他汀治疗后HMG-辅酶A还原酶mRNA丰度增加了7倍，辛伐他汀治疗后增加了2倍（P<0.01）。这些结果表明，辛伐他汀和阿托伐他汀具有不同的半衰期，这可能会影响HMG-辅酶A还原酶mRNA水平。禁食期间辛伐他汀使还原酶活性增加可能与其稳定酶的作用有关。相比之下，阿托伐他汀可能由于其较长的半衰期，延长了对HMG-辅酶A还原酶活性的抑制，并导致mRNA合成增加幅度更大。
