MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents

• Published in: Cancer chemotherapy and pharmacology Vol. 64; no. 1; pp. 183 - 188
• Main Authors: Woodahl, Erica L, Crouthamel, Matthew H, Bui, Tot, Shen, Danny D, Ho, Rodney J. Y
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.06.2009; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; Biological Transport - genetics; Cancer Research; Cells, Cultured; Drug Resistance, Neoplasm; Epithelial Cells - metabolism; Genes, MDR - genetics; Humans; LLC-PK1 Cells; Medical sciences; Medicine; Medicine & Public Health; Oncology; Permeability; Pharmacology. Drug treatments; Pharmacology/Toxicology; Polymorphism, Single Nucleotide; Short Communication; Swine; Cancer chemotherapy; P-Glycoprotein; Pharmacogenomics; Transepithelial permeability; Antineoplastic agent; Genetic variability; ABCB1; Genomics; P Glycoprotein; Genotype; Permeability; Malignant tumor; Chemotherapy; Sensitivity; MDR1; Treatment; MDR-1 gene; Genetics; Cancer; Polymorphism
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-008-0906-4

Purpose P-glycoprotein (P-gp), encoded by MDR1 (or ABCB1), is important in anticancer drug delivery and resistance. We evaluated alterations in P-gp-mediated transport of anticancer agents due to the MDR1 G1199A polymorphism. Methods Using stable recombinant epithelial cells expressing wild-type (MDR1 wt ) or G1199A (MDR1 ₁₁₉₉A ), anticancer drug sensitivity and transepithelial permeability were evaluated. Results The recombinant cells MDR1 wt and MDR1 ₁₁₉₉A displayed comparable doxorubicin resistance. However, MDR1 ₁₁₉₉A cells displayed greater resistance to vinblastine, vincristine, paclitaxel, and VP-16 (11-, 2.9-, 1.9-, and 2.9-fold, respectively). Alterations in transepithelial permeability paralleled these changes. Efflux of doxorubicin was similar between MDR1 wt - and MDR1 ₁₁₉₉A -expressing cells, while P-gp-mediated transport was greater for vinblastine and vincristine in MDR1 ₁₁₉₉A cells (2.9- and 2.0-fold, respectively). Conclusions The occurrence and magnitude of the MDR1 G1199A effect is drug specific. Overall, the MDR1 G1199A polymorphism may impact anticancer efficacy through modulation of drug distribution and delivery to target tumor cells.