Genetic Determinants of ABCB1 Promoter Activity and Their Effects on Environmental Exposure

Abstract

In utero exposure to xenobiotics, including medications and environmental agents, can lead to developmental and behavioral problems as well as cancer later in life. Efflux transporters, which are highly expressed in the human placenta, are key regulators of placental xenobiotic transfer from the maternal to the fetal circulation. A major placental efflux transporter is P-gp, which is encoded by the ABCB1 gene. Many medications prescribed to pregnant women, such as antibiotics for acute illness or medications used to treat chronic diseases including asthma and diabetes, are P-gp substrates. Variability in placental P-gp expression and activity could, therefore, pose a challenge to physicians as it could significantly impact maternal and fetal exposure to medications that are P-gp substrates. There are many SNPs in the ABCB1 promoter but their effect on ABCB1 transcription and subsequent P-gp expression remains unclear. In the genome, SNPs seldom exist as independent variants, but rather form specific combinations or haplotypes due to linkage disequilibrium (correlation) between them. Importantly, recent data from our laboratory indicates the phenotypic effects of individual SNPs are not always consistent but instead are haplotype dependent. The data generated from the studies herein offer important information on the role of genetic variability on the activity of the ABCB1 promoter. These studies provide a detailed sequence information for the ABCB1 promoter haplotypes in a mixed ethnic/racial population and demonstrate the effects from an individual SNP are not always consistent but differ in a haplotype-specific manner. One potential mechanism driving the promoter activity was explored, and we determined that transcription factors bind to the ABCB1 promoter in a haplotype-dependent manner. Finally, it was identified that ABCB1 promoter activity in response to both acute and chronic bisphenol exposures is haplotype-dependent. This information clearly demonstrates that ABCB1 haplotypes, rather than individual SNPs, affect its promoter activity and could thus play a significant role in the expression of placental P-gp, ultimately having significant public health implications, particularly for pregnant women treated with P-gp-substrate medications.