Gender-Specific and Developmental Influences on the Expression of Rat Organic Anion Transporters

Buist, Susan C. N.; Cherrington, Nathan J.; Choudhuri, Supratim; Hartley, Dylan P.; Klaassen, Curtis D.

doi:10.1124/jpet.301.1.145

Cited by 170 publications

(180 citation statements)

References 24 publications

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“…Oat3 mRNA has also been found in rat liver, albeit at relatively low levels; however, hepatic expression was not observed in mice [52,56,64,65]. Although mice appear to exhibit a female predominance (2-fold) in renal expression of Oat3 message, no such difference is apparent in rat [55,64,65]. Deletion of Oat3 resulted in impaired renal basolateral uptake of organic anions.…”

Section: Oat2 (Slc22a7)mentioning

confidence: 96%

“…Both genders of rat displayed comparable liver expression of Oat2 message, but exhibited substantial renal differences. That is, the Oat2 mRNA level in female kidney was several times that of males [64,65]. Likewise, reports on Oat2/ OAT2 localization within the kidney are conflicting, although true species differences cannot be ruled out.…”

Section: Oat2 (Slc22a7)mentioning

confidence: 99%

“…Further, whether gender-dependent expression (discussed below) is related to Oat2's importance in the homeostasis of female-predominant substrates remains unclear. Kidney and liver expression of Oat2/OAT2 message was detected in mice, rats and humans; and in rat and mouse choroid plexus [18,52,[62][63][64][65]. However, there are contrasting studies on hepatic mRNA expression of Oat2 in mice, with one study detecting Oat2 message strictly in females, and another reporting expression in both genders, albeit 2-fold higher in males [55,64].…”

Section: Oat2 (Slc22a7)mentioning

confidence: 99%

“…Oat3/OAT3 mRNA has been identified in the blood-brain barrier endothelium, the lining of ventricles in the brain (choroid plexus) and kidney [52,[66][67][68]. Oat3 mRNA has also been found in rat liver, albeit at relatively low levels; however, hepatic expression was not observed in mice [52,56,64,65]. Although mice appear to exhibit a female predominance (2-fold) in renal expression of Oat3 message, no such difference is apparent in rat [55,64,65].…”

Section: Oat2 (Slc22a7)mentioning

confidence: 99%

See 3 more Smart Citations

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

VanWert

Gionfriddo

Sweet

2009

Biopharm & Drug Disp

222

238

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Our understanding of the mechanisms behind inter-and intra-patient variability in drug response is inadequate. Advances in the cytochrome P450 drug metabolizing enzyme field have been remarkable, but those in the drug transporter field have trailed behind. Currently, however, interest in carrier-mediated disposition of pharmacotherapeutics is on a substantial uprise. This is exemplified by the 2006 FDA guidance statement directed to the pharmaceutical industry. The guidance recommended that industry ascertain whether novel drug entities interact with transporters. This suggestion likely stems from the observation that several novel cloned transporters contribute significantly to the disposition of various approved drugs. Many drugs bear anionic functional groups, and thus interact with organic anion transporters (OATs). Collectively, these transporters are nearly ubiquitously expressed in barrier epithelia. Moreover, several reports indicate that OATs are subject to diverse forms of regulation, much like drug metabolizing enzymes and receptors. Thus, critical to furthering our understanding of patient-and condition-specific responses to pharmacotherapy is the complete characterization of OAT interactions with drugs and regulatory factors. This review provides the reader with a comprehensive account of the function and substrate profile of cloned OATs. In addition, a major focus of this review is on the regulation of OATs including the impact of transcriptional and epigenetic factors, phosphorylation, hormones and gender.

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Section: Oat2 (Slc22a7)mentioning

confidence: 96%

Section: Oat2 (Slc22a7)mentioning

confidence: 99%

Section: Oat2 (Slc22a7)mentioning

confidence: 99%

Section: Oat2 (Slc22a7)mentioning

confidence: 99%

See 2 more Smart Citations

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

VanWert

Gionfriddo

Sweet

2009

Biopharm & Drug Disp

222

238

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“…Therefore, among 63 patients, we focused on 23 males with RCC who had neither complications of renal failure nor diabetes, because these diseases and gender differences were reported to affect the mRNA levels of SLC22A (Urakami et al 1999;Buist et al 2002;Ji et al 2002;Thomas et al 2003;Sakurai et al 2004;Monica Torres et al 2005). The OCT2 mRNA level of the hetero-or homozygote for -578_-576delAAG was slightly decreased compared with that of the wild type, but this difference was not significant (p = 0.1462; Fig.…”

Section: Identification Of Snps In the Promoter Regions Of Oct2 Oat3mentioning

confidence: 99%

Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney

et al. 2008

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Organic cation transporters (OCTs) and organic anion transporters (OATs) (SLC22A family) play crucial roles in the renal secretion of various drugs. Messengar ribonucleic acid (mRNA) expression of transporters can be a key factor regulating interindividual differences in drug pharmacokinetics. However, the source of variations in mRNA levels of transporters is unclear. In this study, we focused on single nucleotide polymorphisms (SNP) in the promoter region [regulatory SNPs (rSNPs)] as candidates for the factor regulating mRNA levels of SLC22A. We sequenced the promoter regions of OCT2 and OAT1-4 in 63 patients and investigated the effects of the identified rSNPs on transcriptional activities and mRNA expression. In the OCT2 promoter region, one deletion polymorphism (-578_-576delAAG) was identified; -578_-576delA-AG significantly reduced OCT2 promoter activity (p \ 0.05), and carriers of -578_-576delAAG tend to have lower OCT2 mRNA levels, but the difference is not significant. There was no rSNP in the OAT1 and OAT2 genes. The five rSNPs of OAT3 and one rSNP of OAT4 were unlikely to influence mRNA expression and promoter activity. This is the first study to investigate the influences of rSNPs on mRNA expression of SLC22A in the kidney and to identify a regulatory polymorphism affecting OCT2 promoter activity.

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Toxicokinetics in Support of Drug Development

Eichenbaum

Subrahmanyam²,

Tonelli

2010

Early Drug Development

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Gender-Specific and Developmental Influences on the Expression of Rat Organic Anion Transporters

Abstract: Rat organic anion transporter 1 (Oat1), Oat2, and Oat3,

Cited by 170 publications

References 24 publications

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney

Toxicokinetics in Support of Drug Development

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