Bergstrom J D, Bostedor R G, Rew D J, Geissler W M, Wright S D, Chao Y S
Department of Biochemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA.
Biochim Biophys Acta. 1998 Jan 23;1389(3):213-21. doi: 10.1016/s0005-2760(97)00182-3.
We have compared the cellular responses to simvastatin (Simva) and atorvastatin (Atorva), two potent HMG-CoA reductase inhibitors. The two drugs exhibited similar IC50's for inhibition of either rat or human reductase, and single oral dosing in rats showed the compounds to be nearly equipotent at inhibiting hepatic cholesterol synthesis. Treatment of rats with Simva or Atorva in the feed for four days yielded comparable inductions of hepatic reductase activity and reductase protein. For example, 0.05% Simva induced reductase activity 27.3 +/- 9.1 fold and 0.05% Atorva induced activity 26.9 +/- 4.7 fold. This adaptive response was also studied in HepG2 cells, a human hepatoblastoma line, cultured for 24 h in delipidated serum and then for an additional 24 h with Simva or Atorva. Over a broad range (10 nM-10 microM), both drugs caused similar inductions of reductase activity, reductase protein, and reductase mRNA. Under all conditions, the drugs induced similar changes in the ratio of mRNA/protein suggesting that Simva and Atorva have similar effects on both transcriptional and post-transcriptional regulatory machinery. Moreover, reductase in cells treated with Simva or Atorva for 22 h responded similarly to subsequent challenge with 25-hydroxycholesterol. Finally, we measured the ability of the two reductase inhibitors to reduce ApoB secretion by HepG2 cells. Simva and Atorva at 0.5 microM inhibited ApoB secretion nearly identically, 38% and 42% respectively. We conclude that these two drugs induce similar adaptive responses in cells and that their actions are qualitatively and mechanistically identical. Human studies have shown that plasma is cleared of Atorva much more slowly than it is of Simva. The large pharmacokinetic difference in man, rather than some difference in mechanism, is the most likely explanation for the finding that the equipotent dose ratio for cholesterol lowering in humans of Simva to Atorva is about 2/1.
我们比较了两种强效HMG-CoA还原酶抑制剂辛伐他汀（Simva）和阿托伐他汀（Atorva）的细胞反应。这两种药物对大鼠或人还原酶的抑制作用表现出相似的半数抑制浓度（IC50），并且在大鼠中单次口服给药显示这两种化合物在抑制肝脏胆固醇合成方面几乎具有同等效力。在饲料中用Simva或Atorva处理大鼠四天，可产生相当的肝脏还原酶活性和还原酶蛋白诱导作用。例如，0.05%的Simva诱导还原酶活性27.3±9.1倍，0.05%的Atorva诱导活性26.9±4.7倍。在人肝癌细胞系HepG2细胞中也研究了这种适应性反应，该细胞系在脱脂血清中培养24小时，然后再用Simva或Atorva培养24小时。在很宽的浓度范围（10 nM - 10 μM）内，两种药物引起的还原酶活性、还原酶蛋白和还原酶mRNA的诱导作用相似。在所有条件下，药物诱导的mRNA/蛋白比值变化相似，表明Simva和Atorva对转录和转录后调控机制具有相似的作用。此外，用Simva或Atorva处理22小时的细胞中的还原酶对随后用25-羟基胆固醇进行的刺激反应相似。最后，我们测量了这两种还原酶抑制剂降低HepG2细胞载脂蛋白B（ApoB）分泌的能力。0.5 μM的Simva和Atorva对ApoB分泌的抑制作用几乎相同，分别为38%和42%。我们得出结论，这两种药物在细胞中诱导相似的适应性反应，并且它们的作用在性质和机制上是相同的。人体研究表明，阿托伐他汀在血浆中的清除速度比辛伐他汀慢得多。人类中这种巨大的药代动力学差异，而非机制上的某些差异，最有可能解释辛伐他汀与阿托伐他汀在人类中降低胆固醇的等效剂量比约为2/1这一发现。
