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Consistent with its expression in the prostate and intestine, single nucleotide variants in hOCT3 have been linked in genome‐wide association studies (GWAS) to prostate cancer and colorectal cancer [50, 51]. In an Asian population, a single nucleotide variant (SNV) within intron 5 of SLC22A3 is associated with prevalence of distal colon cancer [2, 51].

Missense variants in OCT3 are rare. For example, nine nonsynonymous SNPs have been identified and are rare in most investigated populations, with the exception of p.T44M, which has a minor allele frequency (MAF) of 0.017 in African Americans [2]. Variants p.M370I, p.T400I, and p.V423F have functional consequences for OCT3 activity. Specifically, p.M370I reduces norepinephrine uptake by 40% and p.T400I and p.V423F reduce OCT3 V _max for metformin uptake [2, 52]. The impact of these nonsynonymous SNPs on the pharmacokinetics and/or pharmacodynamics of metformin have not been evaluated.

In addition to the missense variants, a number of variants have been identified in the promoter region of OCT3. In particular, eight SNPs with MAFs between 0.01 and 0.29 have been detected in the noncoding promoter region of hOCT3 [2]. Notably, one SNP in the proximal promoter, −2G>A has functional consequences, resulting in decreased transcription of hOCT3 compared with the −2A>G ancestral allele. One SNP (rs2076828, C>G) has been associated in candidate gene studies with reduced metformin response in healthy individuals [2].