Function of the MRP Family

描述(申请人提供)：MRP1和MRP2是ABC转运体MRP家族的创始成员，是药物外排泵，在细胞对抗癌药物的耐药性和药物分配中发挥重要作用。这两个泵现在被认为是一个多基因家族的一部分，该家族有9个成员。我的实验室和其他实验室最近的研究已经确定，新发现的三个被检测的家族成员，MRP3，MRP4和MRP5，也是参与细胞抗癌药物耐药的药物泵。MRP3是一种谷胱甘肽和葡萄糖醛酸结合的外排泵，具有对依托泊苷和甲氨蝶呤产生耐药性的功能，也可能有助于这些药物的口服生物利用度，以及在胆汁淤积条件下参与保护肝细胞，防止这些药物被挤出到胆汁中。MRP4和MRP5是环核苷酸外排泵，细胞将它们作为核苷酸类似物(如6-巯基嘌呤)的耐药因子，MRP4的耐药谱也包括甲氨蝶呤。这些最新的发展表明，这个家族中至少有3个新成员参与了与癌症化疗药物直接相关的重要领域，并提供了一个令人信服的理由，为什么应该深入调查这个家族中每个新发现的成员的活动。在这次竞争性更新中，我们将扩展我们之前对MRP4的调查，并继续分析其他新发现的家庭成员。关于MRP4，我们将确定其对核苷酸类似物产生耐药的生化机制，进一步探索其对癌症化疗药物耐药的可能性，并通过实验小鼠模型评估其作为耐药因子的体内效力。此外，我们将分析两个新发现的家族成员的耐药性和底物选择性，这些成员的结构与MRP4和MRP5的结构相似，表明其功能保守或重叠，其研究可能与我们同时进行的MRP4研究相配合。这些实验应该会为这一复杂的不寻常泵家族影响癌症治疗的潜力提供一个更完整的图景。

DESCRIPTION (provided by applicant): MRP1 and MRP2, the founding members of the MRP family of ABC transporters, are drug efflux pumps that play prominent roles in cellular resistance to anticancer agents and in drug distribution. These two pumps are now known to be part of a multigene family that extends to 9 members. Recent studies in my laboratory and others have determined that the first three of the newly identified family members to be examined, MRP3, MRP4 and MRP5, are also drug pumps involved in cellular resistance to anticancer agents. MRP3 is a glutathione and glucuronate conjugate efflux pump that has the facility for conferring resistance to etoposide and methotrexate, and may also contribute to the oral bioavailability of these agents, as well as participate in the defense of hepatocytes during cholestatic conditions that prevent these agents from being extruded into the bile. MRP4 and MRP5 are cyclic nucleotide efflux pumps that are deployed by the cell as resistance factors for nucleotide analogs such as 6-mercaptopurine, and the resistance profile of MRP4 includes methotrexate as well. These recent developments have disclosed that at least 3 of the new members of this family are involved in important areas that relate directly to cancer chemotherapeutic agents, and provide a compelling reason why the activities of each of the newly identified members of this family should be investigated in depth. In this competitive renewal we will extend our previous investigation of MRP4 and continue our analysis of other newly identified family members. With regard to MRP4, we will determine the biochemical mechanism by which it confers resistance to nucleotide analogs, further explore its potential for conferring resistance to cancer chemotherapeutic agents, and assess its in vivo potency as a resistance factor by the use of experimental mouse models. In addition, we will analyze the drug resistance capabilities and substrates selectivities of two of the newly identified family members whose structural resemblance to MRP4 and MRP5 suggests conserved or overlapping functions and whose investigation may synergize with our concurrent studies on MRP4. These experiments should provide a more complete picture of the potential for this complex family of unusual pumps to impact cancer treatment.