Regulation of Mouse Organic Anion-Transporting Polypeptides (Oatps) in Liver by Prototypical Microsomal Enzyme Inducers That Activate Distinct Transcription Factor Pathways

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108

ABSTRACT:Multidrug resistance (Mdr) transporters are ATP-binding cassette transporters that efflux amphipathic cations from cells and protect tissues from xenobiotics. Unfortunately, Mdr transporters also efflux anticancer drugs from some tumor cells, resulting in multidrug resistance. There are two groups of Mdrs in mice: group I includes Mdr1a and Mdr1b that transport xenobiotics, whereas group II is Mdr2, a flipase that facilitates phospholipid excretion into bile. Little is known about the regulation of Mdr genes in vivo. The purpose of this study was to determine tissue distribution, gender differences, ontogeny, and chemical induction of Mdrs in mice. The mRNA of Mdr1a is highest in gastrointestinal tract, Mdr1b in ovary and placenta, and Mdr2 in liver. Both Mdr1a and Mdr1b in kidney show female-predominant expression patterns due to repression by androgens. The ontogeny of mouse Mdr1a in duodenum and brain as well as Mdr1b in brain, kidney, and liver all share a similar developmental pattern: low expression at birth, followed by a gradual increase to mature levels at approximately 30 days of age. In contrast, Mdr2 mRNA in liver is markedly up-regulated at birth, which returns to low levels by 5 days of age and then gradually increases to mature levels. None of the Mdrs in liver are readily inducible by any class of microsomal enzyme inducers. In conclusion, the three Mdr transporters in mice are expressed in a tissue-specific and age-dependent pattern, there are gender differences in expression, and Mdr transporters are inducible by only a few microsomal enzyme inducers.

Section: Regulation Of Mouse Mdr Transporterscontrasting

confidence: 47%

Tissue Distribution, Gender-Divergent Expression, Ontogeny, and Chemical Induction of Multidrug Resistance Transporter Genes (Mdr1a,Mdr1b,Mdr2) in Mice

Cui¹,

Cheng²,

Weaver³

et al. 2008

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108

“…However, this mechanism leads to smaller differences in rosuvastatin kinetics compared with competitive inhibition. We acknowledge that the regulation of OATP1 expression is complex, and other transcription factors such the constitutive androstane receptor, pregnane X receptor, peroxisome proliferator-activated receptor, farnesoid X receptor, and small heterodimer partner may play a role in regulating OATP1B1 expression as these factors have been found in the promoter and enhancer region of Oatp2 in rats (Cheng et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

Hepatic Nuclear Factor 1α Inhibitor Ursodeoxycholic Acid Influences Pharmacokinetics of the Organic Anion Transporting Polypeptide 1B1 Substrate Rosuvastatin and Bilirubin

He¹,

Zhang²,

Tu³

et al. 2008

ABSTRACT:Expression of the organic anion transporting polypeptide 1B1 (OATP1B1) is regulated by transcription factor hepatic nuclear factor (HNF) 1␣. The aim of this study was to investigate the effect of ursodeoxycholic acid (UDCA), an inhibitor of transcription factor HNF1␣, on rosuvastatin and bilirubin kinetics in human healthy volunteers. Both substances are substrates of OATP1B1. Twelve subjects with OATP1B1*1b/*1b genotype predicting high transport activity were recruited for this randomized, crossover study. Each subject received a single p.o. dose of 20 mg of rosuvastatin after 14 days of p.o. intake of either 500 mg of UDCA or placebo. Plasma concentrations of rosuvastatin were determined on days 15 to 18 of each study period. Subjects were randomly assigned to UDCA or placebo group. Intake of UDCA led to a significant increase in rosuvastatin area under the curve (AUC) 0-72 from 128.5 ng/ml ⅐ h to 182.1 ng/ml ⅐ h (P ‫؍‬ 0.008) compared with the control group. The oral clearance decreased from 155.2 l/h with placebo to 109.8 l/h with UDCA. In addition, the mean values of total bilirubin, conjugated bilirubin, and unconjugated bilirubin significantly increased to 139 ؎ 39% (P ‫؍‬ 0.003), 127 ؎ 29% (P ‫؍‬ 0.005), and 151 ؎ 52% (P ‫؍‬ 0.004), respectively, after UDCA treatment. These results in healthy volunteers confirm the findings from in vitro studies that UDCA inhibits OATP1B1 activity by inhibition of the transcription factor HNF1␣. They highlight a novel mechanism of OATP1B1-based interaction that is mediated by transcription factor HNF1␣.

“…After several incubation and washing steps, streptavidin-conjugated R-phycoerythrin fluorescence was analyzed by a Bio-Plex 200 system array reader interfaced with Bio-Plex data manager software 5.0 (Bio-Rad Laboratories, Hercules, CA). The majority of the genes quantified in the current study have been previously characterized by our laboratory (Cheng et al, 2005;Klaassen, 2006, 2008a,b;Buckley and Klaassen, 2007;Cheng and Klaassen, 2009). Details of the plex sets used in the current study can be found at www.panomics.com with the following numbers: 21073, 21150, 21152, 21153, 21174, and 21175.…”

Section: Methodsmentioning

confidence: 99%

Energy Restriction Does Not Compensate for the Reduced Expression of Hepatic Drug-Processing Genes in Mice with Aging

Zhang¹,

Saupe²,

Klaassen³

2010

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ABSTRACT:Liver is the major organ that eliminates xenobiotics from the body, a process that is accomplished by a series of drug-processing genes (DPGs). These genes encode transporters on both basolateral and apical membranes of hepatocytes, as well as phase I and II enzymes. The current study compares the expression of hepatic DPGs in adult and aged mouse livers and explores the potential effects of energy restriction (ER) on these genes during aging. Of 79 quantified hepatic DPGs, 52 were expressed lower in 24-monthold aged mice than in 12-month-old adult mice. Furthermore, the mRNA expression of multiple xenobiotic-activated transcription factors also decreased with age. Six-month ER exerted less of an effect on the hepatic DPGs than did aging. ER increased the mRNAs of two and decreased the mRNAs of nine DPGs in adult mice. In aged mice, ER increased the mRNAs of 10 and decreased the mRNAs of 5 DPGs. The only mRNA that was increased by both ER and aging was Gstm3. ER increased the mRNAs of Cyp2b10, Ugt1a9, Gsta1, and Oatp1a4 only in adult mice and decreased the mRNAs of Aldh6a1, Pon3, Ugt1a1, Sult1a1, and Atp8b1 only in aged mice. In summary, the reduced mRNA expression of hepatic DPGs in aged mice indicates decreased drug-processing capability, whereas ER did not compensate for the global reduction of hepatic DPG expression in aged mice. The hepatic transcription factors are likely to mediate the changes in hepatic DPG expression during aging and ER.The geriatric population is rapidly increasing in the world. The proportion of persons aged 60 or older is projected to reach 22% of the global population in 2050, with 33% in more developed regions and 20% in less developed regions (United Nations Population Ageing and Development 2009, http://www.un.org/esa/population/ publications/ageing/ageing2009chart.pdf). Health care for this population presents a major medical and economic problem. The elderly population is more susceptible to various diseases, and they often take several drugs at the same time. Liver, the major organ for drug elimination from the body, exhibits decreased volume, diminished hepatobiliary functions, declined phase I drug metabolism capability, and increased or decreased expression of a variety of proteins in the elderly population (Schmucker, 2005).Liver metabolizes endogenous and exogenous compounds (nutrients and drugs), as well as maintains energy balance in the body. Numerous liver functions are accomplished by proteins encoded by a series of drug-processing genes (DPGs), which include basolateral uptake transporters, phase I and II enzymes, and apical and basolateral efflux transporters.Hepatocytes have transporters on both their basolateral and apical sides to remove xenobiotics from intestine-derived portal blood and to excrete them or their metabolites into bile or blood. Uptake solute carriers include organic anion-transporting polypeptides (Oatps), sodium/taurocholate-cotransporting polypeptide (Ntcp), organic cation transporters (Octs), organic anion transporters (Oats), and so...