Читать книгу Drug Transporters - Группа авторов - Страница 35

In human, OCT1 is predominantly expressed in hepatocytes. Thus, the SLC22A1 gene is suggested to be regulated by the liver‐enriched transcription factors, such as hepatocyte nuclear factor 4a (HNF4a), CCAAT/enhancer binding proteins α and β, hepatocyte nuclear factor 1a (HNF1a) and 3c (HNF3c). Two co‐operating HNF4a response elements have been identified between nucleotides ‐1479 and ‐1441 of the 5′‐flanking regions of the SLC22A1 gene, which are upstream of the transcription initiation sites. In electrophoretic mobility shift assay (EMSA), recombinant HNF4a directly interacts with both sites. Mutation of these sites in SLC22A1 promoter luciferase reporter constructs abolish transactivation [21]. These motifs are conserved in primates, but not rodents, indicating different patterns of SLC22A1/Slc22a1 gene regulation in these species [22]. In addition, upstream stimulating factors USF1 and USF2 have been identified to regulate basal hepatic expression of OCT1 via a cognate E‐box [22]. OCT1 expression can be modulated by ligand‐dependent nuclear receptors such as pregnane X receptor, farnesoid X receptor, constitutive androstane receptor, glucocorticoid receptor or peroxisome proliferator‐activated receptor α and γ. In addition, the transcription expression level of OCT1 can be regulated by epigenetic methylation [2]. Moreover, OCT1 can be subject to post‐translational modulation. Stimulation of either protein kinase A(PKA) or PKC increases uptake of the fluorescent compound ASP⁺ in HEK‐293 cells stably transfected with rat OCT1 [1]. However, this effect may be species‐dependent [23]. As with rOCT1, hOCT1 appears to be positively regulated by the p56lck tyrosine kinase, as evidenced by reduced hOCT1 activity after treatment with aminogenistein. Human OCT1 has further been shown to be regulated by the Ca²⁺/calmodulin complex, which appears to affect the affinity of the tested substrates [23], possibly due to phosphorylation of the OCT1 protein.

FIGURE 2.2 (a) Alternating‐access transport model for translocation of substrates by organic cation and zwitterion transporters. (b) Types of transport mechanisms for organic cation and zwitterion transporters. Created with BioRender.com.