Gene expression and regulation of drug transporters in the intestine and kidney

Takato, Tsuyoshi; Inui, Kentaro

doi:10.1016/j.bcp.2006.10.010

Cited by 75 publications

(46 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since the expression of OCT2, and not OCT1, is higher at the basolateral site of the renal proximal tubule cells (Urakami et al, 1998;Karbach et al, 2000;Terada and Inui, 2007), OCT2 appears to promote the incorporation of CDDP into renal cells. On the other hand, mice lacking the Slc47a1 gene have exhibited severe CDDP-induced nephrotoxicity (Nakamura et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Renal Circadian Clock Regulates the Dosing-Time Dependency of Cisplatin-Induced Nephrotoxicity in Mice

et al. 2014

View full text Add to dashboard Cite

Cisplatin, cis-diamminedichloro-platinum (CDDP), is a widely used anticancer agent, the clinical applications of which have been limited by severe nephrotoxicity. Although dosing timedependent differences in CDDP-induced nephrotoxicity have been reported in both humans and laboratory animals, the underlying mechanism remains unknown. In the present study, we investigated the molecular mechanism for the dosing-time dependency of the nephrotoxic effect of CDDP in mice. CDDPinduced nephrotoxicity was significantly attenuated by injecting CDDP at times of the day when its renal clearance was enhanced. The dosing-time dependency of the nephrotoxic effect was parallel to that of CDDP incorporation into renal DNA. Two types of transporters, organic cation transporter 2 (OCT2, encoded by Slc22a2) and multidrug and toxin extrusion 1 (MATE1, encoded by Slc47a1), are responsible for the renal excretion of CDDP. The expression of OCT2, but not MATE1, exhibited a significant time-dependent oscillation in the kidneys of mice. The circadian expression of OCT2 was closely related to the dosing-time dependency of CDDP incorporation into renal DNA. Molecular components of the circadian clock regulated the renal expression of Slc22a2 mRNA by mediating peroxisome proliferator-activated receptor-a, which resulted in rhythmic oscillations in OCT2 protein levels. These findings indicate a clock-regulated mechanism of dosing time-dependent changes in CDDP-induced nephrotoxicity and also suggest a molecular link between the circadian clock and renal xenobiotic excretion.

show abstract

Section: Discussionmentioning

confidence: 99%

Renal Circadian Clock Regulates the Dosing-Time Dependency of Cisplatin-Induced Nephrotoxicity in Mice

et al. 2014

View full text Add to dashboard Cite

show abstract

“…OCT2 (SLC22A2), OAT1 (SLC22A6), OAT2 (SLC22A7), OAT3 (SLC22A8), and OAT4 (SLC22A11) are highly expressed in the human kidney cortex (Motohashi et al 2002;Terada and Inui 2007) and are known to transport clinically important drugs such as biguanides, histamine (H 2 ) receptor antagonists, anticancer drugs, antivirals, cephalosporin antibiotics, and nonsteroidal anti-inflammatory drugs (Burckhardt and Burckhardt 2003;Rizwan and Burckhardt 2007;Koepsell et al 2007).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…We were the first to report that the transcriptional regulation of intestinal fatty acid transport systems is coordinately regulated with intracellular fatty acid metabolism by a nutrient nuclear receptor, peroxisome proliferator-activated receptor (PPAR)a. 6) Most studies on transcriptional regulation of the sugar transporters and major drug transporters in the intestine have focused on the mechanisms involved in basal regulation 7,8) and few papers have reported the molecular basis for their physiological responses. 9) The H ϩ /peptide co-transporter 1 (Pept1/Slc15A) on the brush-border membranes of intestinal epithelia has been studied the most, and the amount of Pept1 protein is known to be regulated under various physiological conditions.…”

mentioning

confidence: 99%

PPAR.ALPHA. Agonists Positively and Negatively Regulate the Expression of Several Nutrient/Drug Transporters in Mouse Small Intestine

Hirai

Fukui

Motojima

2007

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

A systematic analysis to examine the effects of peroxisome proliferator-activated receptor (PPAR)a a agonists on the expression levels of all the nutrient/drug plasma-membrane transporters in the mouse small intestine was performed. Transporter mRNAs that were induced or repressed by two independent PPARa a-specific agonists were identified by a genome-wide microarray method, and the changes were confirmed by real-time PCR using RNA isolated from the intestines and livers of wild-type and PPARa a-null mice. Expression levels of seven nutrient/drug transporters (Abcd3, Octn2/Slc22a5, FATP2/Slc27a2, Slc22a21, Mct13/Slc16a13, Slc23a1 and Bcrp/ Abcg2) in the intestine were up-regulated and the expression level of one (Mrp1/Abcc1) was down-regulated by PPARa a; although the previously report that the H ؉ /peptide co-transporter 1 (Pept1) is up-regulated by PPARa a was not replicated in our study. We propose that the transport processes can be coordinately regulated with intracellular metabolism by nutrient nuclear receptors.

show abstract

Gene expression and regulation of drug transporters in the intestine and kidney

Cited by 75 publications

References 85 publications

Renal Circadian Clock Regulates the Dosing-Time Dependency of Cisplatin-Induced Nephrotoxicity in Mice

Renal Circadian Clock Regulates the Dosing-Time Dependency of Cisplatin-Induced Nephrotoxicity in Mice

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

PPAR.ALPHA. Agonists Positively and Negatively Regulate the Expression of Several Nutrient/Drug Transporters in Mouse Small Intestine

Contact Info

Product

Resources

About