aDepartment of Medical and Health Sciences, Division of Drug Research/Clinical Pharmacology, Faculty of Health Sciences bDepartment of Clinical and Experimental Medicine, Linköping University cDivision of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Department of Clinical Pharmacology, County Council of Östergötland dDepartment of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
Pharmacogenet Genomics. 2014 Jan;24(1):52-61. doi: 10.1097/FPC.0000000000000022.
The tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ATP-binding cassette subfamily G member 2 (ABCG2). Variations in ABCG2 activity might influence pharmacokinetics and therapeutic outcome of TKIs. The role of ABCG2 single-nucleotide polymorphisms (SNPs) in TKI treatment is not clear and functional in-vitro studies are lacking. The aim of this study was to investigate the consequences of ABCG2 SNPs for transport and efficacy of TKIs [imatinib, N-desmethyl imatinib (CGP74588), dasatinib, nilotinib, and bosutinib].
ABCG2 SNPs 34G>A, 421C>A, 623T>C, 886G>C, 1574T>G, and 1582G>A were constructed from ABCG2 wild-type cDNA and transduced to K562 cells by retroviral gene transfer. Variant ABCG2 expression in cell membranes was evaluated and the effects of ABCG2 SNPs on transport and efficacy of TKIs were measured as the ability of ABCG2 variants to protect against TKI cytotoxicity.
Wild-type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided better protection against CGP74588 than its parent compound, imatinib. ABCG2 421C>A, 623T>C, 886G>C, and 1574T>G reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib, and nilotinib cytotoxicity.
These findings show that the ABCG2 SNPs 421C>A, 623T>C, 886G>C, and 1574T>G increase the efficacy of investigated TKIs, indicating a reduced transport function that might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is influenced by ABCG2 expression to a greater extent than the parent compound.
用于治疗慢性髓性白血病的酪氨酸激酶抑制剂（TKI）是三磷酸腺苷结合盒亚家族 G 成员 2（ABCG2）外排转运蛋白的底物。ABCG2 活性的变化可能会影响 TKI 的药代动力学和治疗效果。ABCG2 单核苷酸多态性（SNP）在 TKI 治疗中的作用尚不清楚，也缺乏功能的体外研究。本研究旨在探讨 ABCG2 SNP 对 TKI（伊马替尼、N-去甲基伊马替尼（CGP74588）、达沙替尼、尼洛替尼和博舒替尼）的转运和疗效的影响。
从 ABCG2 野生型 cDNA 构建 ABCG2 SNP 34G>A、421C>A、623T>C、886G>C、1574T>G 和 1582G>A，并通过逆转录病毒基因转移转染至 K562 细胞。评估变体 ABCG2 在细胞膜上的表达，并测量 ABCG2 SNP 对 TKI 转运和疗效的影响，即变体 ABCG2 对 TKI 细胞毒性的保护能力。
野生型 ABCG2 对除博舒替尼以外的所有研究化合物的细胞毒性均具有保护作用。结果发现，ABCG2 表达对 CGP74588 的保护作用优于其母体化合物伊马替尼。ABCG2 421C>A、623T>C、886G>C 和 1574T>G 降低了 ABCG2 的细胞膜表达，并降低了 ABCG2 对伊马替尼、CGP74588、达沙替尼和尼洛替尼细胞毒性的保护作用。
这些发现表明，ABCG2 SNP 421C>A、623T>C、886G>C 和 1574T>G 增加了研究 TKI 的疗效，表明转运功能降低，可能影响体内 TKI 的药代动力学。此外，活性伊马替尼代谢物 CGP74588 比母体化合物更受 ABCG2 表达的影响。
