Kostrubsky V E, Lewis L D, Wood S G, Sinclair P R, Wrighton S A, Sinclair J F
Veterans Administration Medical Center, White River Junction, Vermont 05009, USA.
Toxicol Appl Pharmacol. 1997 Jan;142(1):79-86. doi: 10.1006/taap.1996.8023.
The purpose of this study was to determine if Taxol induced CYP3A in primary cultures of rat hepatocytes and, if so, whether induction of CYP3A would increase acetaminophen toxicity. Taxol caused a concentration-dependent increase in the amount of immunoreactive CYP3A and in the steady-state levels of CYP3A1/DEX but not CYP3A2 mRNA. Similar concentration-dependent increases in toxicity as measured by a decrease in protein synthesis were observed after exposure of cells to acetaminophen for 7 hr whether cells were pretreated with Taxol or dexamethasone. Increased release of lactate dehydrogenase occured after 24 hr exposure to acetaminophen, with no further decreases in protein synthesis than those observed at 7 hr. Increases in acetaminophen toxicity correlated with increased covalent binding of acetaminophen to cellular proteins. Triacetyloleandomycin, a selective inhibitor of CYP3A, completely protected the cells against acetaminophen toxicity in both Taxol- and dexamethasone-pretreated cells and prevented the increase in covalent binding of acetaminophen to cellular proteins. These results demonstrate that Taxol, like dexamethasone, induces CYP3A and that increases in this P450 are responsible for increased acetaminophen toxicity.
本研究的目的是确定紫杉醇是否能在原代培养的大鼠肝细胞中诱导细胞色素P450 3A（CYP3A）的产生，若能诱导，那么CYP3A的诱导是否会增加对乙酰氨基酚的毒性。紫杉醇使免疫反应性CYP3A的量以及CYP3A1/DEX的稳态水平呈浓度依赖性增加，但对CYP3A2 mRNA水平无影响。无论细胞是用紫杉醇还是地塞米松预处理，在细胞暴露于对乙酰氨基酚7小时后，通过蛋白质合成减少来衡量的毒性都出现了类似的浓度依赖性增加。在暴露于对乙酰氨基酚24小时后，乳酸脱氢酶的释放增加，蛋白质合成的减少程度并未超过7小时时观察到的情况。对乙酰氨基酚毒性的增加与对乙酰氨基酚与细胞蛋白质的共价结合增加相关。三乙酰竹桃霉素，一种CYP3A的选择性抑制剂，在紫杉醇和地塞米松预处理的细胞中均能完全保护细胞免受对乙酰氨基酚的毒性，并阻止对乙酰氨基酚与细胞蛋白质共价结合的增加。这些结果表明，紫杉醇与地塞米松一样，能诱导CYP3A的产生，且这种细胞色素P450的增加是对乙酰氨基酚毒性增加的原因。
