Role of SLC10A1 SNPs in regulating cytochrome P450 expression

Abstract

Cytochrome's P450 (CYPs) are a group of enzymes that have a major role in metabolizing drugs, and their variable expression can lead to pharmacokinetic and pharmacodynamic differences within the population. Genetic variants in CYPs have been extensively investigated, but they only explain a part of the interindividual variation in hepatic CYP expression. A recent study has proposed SLC10A1, a bile acid uptake carrier, to be a novel regulator of CYP expression. Hence, we hypothesized that functional SNPs (single nucleotide polymorphisms) in SLC10A1 may have an effect on CYP expression. Towards this end we resequenced all exons, promoter, and 3′‐UTR of SLC10A1 in 98 human livers (43 over‐ and 55 under‐expressing) to look for functional SNPs. We found a total of eight SNPs. An exon 1 synonymous SNP (rs4646285) occurred with a higher frequency in livers overexpressing SLC10A1, whereas a 3′‐UTR SNP (rs45593332) occurred with a higher frequency in the livers underexpressing SLC10A1. The genotypes of rs4646285 correlated with total mRNA of SLC10A1 as well as the downstream target CYP3A4 (p=0.02). An allelic expression imbalance assay demonstrated samples having imbalanced SLC10A1 expression, although none of the SLC10A1 SNPs explained the cause of this imbalance. In conclusion, an exonic SLC10A1 SNP led to increased SLC10A1 mRNA expression and increased CYP3A4 expression and may help explain some of the variation in the pharmacokinetics of CYP3A4 substrate drugs. This work was funded by the Pediatric Oncology Education (POE) summer program at St. Jude Children's Hospital (O.V.).