Abu-Qare Aqel W, Elmasry Eman, Abou-Donia Mohamed B
Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Toxicol Environ Health B Crit Rev. 2003 May-Jun;6(3):279-88. doi: 10.1080/10937400306466.
P-Glycoprotein (P-gp) is a transmembrane protein, playing significant roles in the process of drug discovery and development and in pest resistance to pesticides. P-gp affects absorption, disposition, and elimination of different compounds and is mainly expressed in intestines, liver, kidneys, heart, colon, and placenta. The expression of P-gp in the blood-brain barrier (BBB) has been associated with the restricted access of many compounds to the central nervous system. Generated knockout mice by disruption of mdr 1a gene, encoding for P-gp, showed that this protein was expressed in the BBB. The absence or the low levels of P-gp elevated drug concentrations in tissues and decreased drug elimination. P-gp is responsible for resistance of cells to agents, particularly the anticancer drugs, by removing these drugs from cells. Increased expression of P-gp is implicated in decreased HIV drug availability at certain intracellular sites. The role of P-gp in affecting efficacy and toxicity of environmental toxicants such as pesticides and heavy metals has not been adequately investigated. Studies showed that P-gp contributes to resistance to pesticides in certain pest species, and to decrease toxicity by removing compounds from cells in mammals. Placental drug-transporting P-gp plays a significant role in limiting the transport of toxicants such as potential teratogens to the fetus. Several in vitro or in vivo assays, including using P-gp knockout or naturally deficient mice, were described for testing P-gp modulators. The role of P-gp following concurrent exposure to more multiple compounds needs further research. P-gp modulators should be carefully used, since some modulators that reverse P-gp efflux action in vitro may lead to alterations of tissue function and increase toxicity of xenobiotics in normal tissues. Recent reports from the pharmaceutical studies on the significance of P-gp as transporters in altering the efficacy and toxicity clearly highlight the need for further research in interaction with environmental toxicants.
P-糖蛋白（P-gp）是一种跨膜蛋白，在药物研发过程以及害虫对杀虫剂的抗性方面发挥着重要作用。P-gp影响不同化合物的吸收、分布和消除，主要在肠道、肝脏、肾脏、心脏、结肠和胎盘中表达。血脑屏障（BBB）中P-gp的表达与许多化合物进入中枢神经系统受限有关。通过破坏编码P-gp的mdr 1a基因产生的基因敲除小鼠表明，这种蛋白在血脑屏障中表达。P-gp的缺失或低水平会提高组织中的药物浓度并降低药物消除。P-gp通过将这些药物从细胞中清除，使细胞对药物尤其是抗癌药物产生抗性。P-gp表达增加与某些细胞内位点的HIV药物可用性降低有关。P-gp在影响农药和重金属等环境毒物的功效和毒性方面的作用尚未得到充分研究。研究表明，P-gp有助于某些害虫物种对农药产生抗性，并通过从哺乳动物细胞中清除化合物来降低毒性。胎盘药物转运P-gp在限制潜在致畸剂等毒物向胎儿的转运中起重要作用。描述了几种体外或体内试验，包括使用P-gp基因敲除或天然缺陷小鼠来测试P-gp调节剂。同时接触多种化合物后P-gp的作用需要进一步研究。应谨慎使用P-gp调节剂，因为一些在体外逆转P-gp外排作用的调节剂可能导致组织功能改变并增加正常组织中外源化合物的毒性。药物研究中关于P-gp作为转运蛋白在改变功效和毒性方面的重要性的最新报告清楚地表明，需要进一步研究其与环境毒物的相互作用。
