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Abstract：
The human ABCG2 multidrug transporter plays a crucial role in the absorption and excretion of xeno- and endobiotics; thus the relatively frequent polymorphic and mutant ABCG2 variants in the population may significantly alter disease conditions and pharmacological effects. Low-level or non-functional ABCG2 expression may increase individual drug toxicity, reduce cancer drug resistance, and result in hyperuricemia and gout. In the present work we have studied the cellular expression, trafficking, and function of nine naturally occurring polymorphic and mutant variants of ABCG2. A comprehensive analysis of the membrane localization, transport, and ATPase activity, as well as retention and degradation in intracellular compartments was performed. Among the examined variants, R147W and R383C showed expression and/or protein folding defects, indicating that they could indeed contribute to ABCG2 functional deficiency. These studies and the applied methods should significantly promote the exploration of the medical effects of these personal variants, promote potential therapies, and help to elucidate the specific role of the affected regions in the folding and function of the ABCG2 protein.
摘要：
人ABCG2多药转运体在外源性和内源性物质的吸收和排泄中起着至关重要的作用；因此，人群中相对频繁的多态性和突变型ABCG2变体可能会显着改变疾病状况和药理作用。低水平或无功能的ABCG2表达可能会增加个体药物毒性，减少癌症耐药性，导致高尿酸血症和痛风.在目前的工作中，我们研究了细胞表达，贩运，和ABCG2的九个天然存在的多态性和突变体变体的功能。全面分析了膜的定位，运输,和ATP酶活性，以及在细胞内区室中的保留和降解进行。在检查的变体中，R147W和R383C显示表达和/或蛋白质折叠缺陷，表明它们确实可能导致ABCG2功能缺陷。这些研究和应用方法应大大促进对这些个人变异的医学效果的探索，推广潜在的疗法，并有助于阐明受影响区域在ABCG2蛋白折叠和功能中的特定作用。
