Analyses of coding region polymorphisms in apical and basolateral human organic anion transporter (OAT) genes [OAT1 (NKT), OAT2, OAT3, OAT4, URAT (RST)] Rapid Communication

Abstract

Together, these data suggest that, in order to understand the effect of SNPs in genes of the SLC22 family on drug handling as well as excretion of metabolites like uric acid, it is important to consider the entire set of organic anion transporters. It will be particularly interesting to determine if individuals with nonsynonymous apical and basolateral SNPs have altered handling (and toxicity) of organic anionic drugs and metabolites. Certain OAT family members appear to be under greater evolutionary selection pressure.

Analyses of 5′ regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3)

“…Nevertheless, our data indicate that variation in the noncoding regions of these genes, particularly SLC22A8, may have an impact on human variation in handling of drugs and toxins by the basolateral OATs. Such regulatory polymorphisms are especially important given the low level of nonsynonymous polymorphisms so far observed in coding regions of these genes compared with other members of family such as SLC22A11 and SLC22A12 (Xu et al 2005). Similar considerations apply to understanding the roles of SNPs in this subfamily on uric acid handling in gout, uric acid nephrolithiasis and human variations in serum uric acid, since OAT1, OAT3, and URAT1 are encoded by three genes proposed to regulate renal urate handling (reviewed in Hediger et al 2005).…”

“…Likewise, such polymorphisms could conceivably explain susceptibility to the toxicity of drugs and environmental toxins. Recent studies have thus analyzed coding region polymorphisms in these genes (Xu et al 2005;Bleasby et al 2005;Fujita et al 2005). However, unlike other members of this subfamily such as SLC22A11 (also known as OAT4) and SLC22A12 (also known as URAT1 and originally identified as RST in mouse), there appear to be relatively infrequent nonsynonymous coding region human polymorphisms in SLC22A6 and SLC22A8 (Xu et al 2005).…”

“…Recent studies have thus analyzed coding region polymorphisms in these genes (Xu et al 2005;Bleasby et al 2005;Fujita et al 2005). However, unlike other members of this subfamily such as SLC22A11 (also known as OAT4) and SLC22A12 (also known as URAT1 and originally identified as RST in mouse), there appear to be relatively infrequent nonsynonymous coding region human polymorphisms in SLC22A6 and SLC22A8 (Xu et al 2005). Thus, while some variation in drug/toxin handling might be explained by coding region polymorphisms in these genes, the apparent paucity of such polymorphisms suggests the need to also analyze noncoding region variation in these genes, which might, for example, affect the transcription of SLC22A6 and SLC22A8 and thereby the total levels of functional protein.…”

Farmacogenómica como herramienta fundamental para la medicina personalizada: aplicaciones en la práctica clínica

“…Polimorfismos tales como 3435C>T o 2677G>T en dicho gen se asocian a modificaciones en la concentración de los fárma-cos y causan desde efectos indeseables a falta de acción terapéutica. Del mismo modo, el papel de polimorfismos genéticos en otros transportadores como MRPs (multidrug-resistance proteins), OATs (organic anion-transporters), SCL (solute carrier) y OCTs (organic cation transporters), entre otros, han sido ampliamente investigados, con resultados muy prometedores [45][46][47][48][49][50] . En la Tabla 4 se muestran los polimorfismos conocidos en la actualidad para transportadores de fármacos potencialmente útiles en la personalización fár-maco-terapéutica.…”

Current Updates in the Genetic Polymorphisms of Human Organic Anion Transporters (OATs)

“…To thoroughly investigate individual differences in response to drugs, 96 healthy individuals representing the major ethno geographic divisions were analyzed by Xu et al [50]. Five SNPs were identified in the coding regions of hOAT1, three of which are synonymous (252G>T, 351A>G, and 1233C>T) and found in several ethnic groups (Indo-Pakistani, Japanese, Sub-Saharan African, Ashkenazi Jewish, North Saharan African and Northern European); whereas two nonsynonymous SNPs, 20T>C and 149G>A, were only discovered in the Southeast Asian and Sub-Saharan African population, respectively.…”