Sáenz-Robles M T, Toma D, Cantalupo P, Zhou J, Gong H, Edwards C, Pipas J M, Xie W
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Oncogene. 2007 Aug 2;26(35):5124-31. doi: 10.1038/sj.onc.1210310. Epub 2007 Mar 5.
Toxic compounds such as carcinogens are removed from the body by the action of a series of detoxifying enzymes and transporters expressed in the liver and the small intestine. We have found that intestinal epithelial cells expressing the SV40 large T antigen (TAg) contain significantly lower levels of mRNAs, encoding several drug metabolizing/detoxifying enzymes and transporters compared to their non-transgenic littermates. In addition, TAg blocks the induction of these mRNAs by xenobiotics. The repression depends on an intact LXCXE motif in TAg, suggesting that inactivation of the retinoblastoma (Rb) family of tumor suppressors plays a role in the process. These results imply that a functional Rb pathway in the intestine is necessary for the expression of the detoxification system used to clear carcinogens, and suggest that loss of this tumor suppressor might alter susceptibility to chemical injury. In addition, the effect of TAg on the detoxification pathway appears to be tissue-specific, as its ectopic expression in the liver failed to suppress the P450 enzymes. The TAg-mediated suppression of drug metabolizing/detoxifying enzymes may have broad implications in the metabolism and mechanism of action of both carcinogens and prescription drugs.
诸如致癌物等有毒化合物通过肝脏和小肠中表达的一系列解毒酶和转运蛋白的作用从体内清除。我们发现，与非转基因同窝仔相比，表达SV40大T抗原（TAg）的肠上皮细胞中，编码几种药物代谢/解毒酶和转运蛋白的mRNA水平显著降低。此外，TAg可阻断异生素对这些mRNA的诱导作用。这种抑制作用取决于TAg中完整的LXCXE基序，这表明肿瘤抑制因子视网膜母细胞瘤（Rb）家族的失活在这一过程中发挥了作用。这些结果表明，肠道中功能性的Rb信号通路对于用于清除致癌物的解毒系统的表达是必需的，并提示这种肿瘤抑制因子的缺失可能会改变对化学损伤的易感性。此外，TAg对解毒途径的影响似乎具有组织特异性，因为它在肝脏中的异位表达未能抑制P450酶。TAg介导的对药物代谢/解毒酶的抑制作用可能对致癌物和处方药的代谢及作用机制具有广泛影响。
