Age- and sex-related differences of organic anion-transporting polypeptide gene expression in livers of rats

Hou, Wei-Yu; Xu, Shang‐Fu; Zhu, Qiong-Ni; Lu, Yuan‐Fu; Cheng, Xinjian; Liu, Jie

doi:10.1016/j.taap.2014.08.020

Cited by 30 publications

(18 citation statements)

References 41 publications

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“…The patterns of mRNA and protein expression levels for the three transporters that underwent western blot analysis were similar. The profile of the ontogeny and age-associated expression of these transporters may provide useful information for the disposition of drugs and toxicants in the kidney, similar to our previous study on liver (29). The present study systematically profiled the ontogeny of 12 primary kidney transporters, and to the best of our knowledge, is among the first to profile age-associated variations in transporter expression.…”

Section: Discussionsupporting

confidence: 72%

“…Numerous factors, including age-associated variation, may influence the expression of OATP4C1, thereby altering drug disposition, efficacy and toxicity (1). Our recent study revealed the ontogeny and age-associated alterations of OATP expression in the liver (29), and in the present study, the ontogeny of OATP4C1, the primary OATP in the kidney, was characterized.…”

Section: Discussionsupporting

confidence: 50%

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Age-associated differences in transporter gene expression in kidneys of male rats

Wang

et al. 2016

Molecular Medicine Reports

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Kidney transporters are involved in the secretion and reabsorption of endogenous and exogenous molecules. Numerous factors may influence their expression and affect drug disposition, efficacy and toxicity. The present study aimed to examine the development‑ and age‑associated variations in primary renal transporters in rats, including 6 uptake transporters: Organic anion transporter (OAT) 1 and 3, organic cation transporter (OCT) 1, 2 and 3 and organic anion‑transporting polypeptide (OATP) 4C1, and 6 efflux transporters: Multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), multidrug resistance‑associated protein (MRP) 2 and 4, and multidrug and toxin extrusion protein (MATE) 1 and 2‑K. Kidneys from male Sprague Dawley rats during development (‑2, 1, 7, 14 and 21 days), maturation (28, 35 and 60 days) and aging (180, 540 and 850 days) were collected and total RNA was extracted, purified and subjected to reverse transcription‑quantitative polymerase chain reaction analysis. Total proteins were extracted for western blot analysis. OAT1 and 3, OCT1, BCRP, MRP2 and 4 and MATE2‑K expression levels were low in fetal kidneys, increased gradually following birth and markedly increased on maturation and adulthood. High levels were maintained until 850 days. OCT2, OATP4C1, Mdr1b and MATE1 expression levels were low in fetal kidneys, increased gradually following birth, and increased markedly on weaning, maturation and adulthood; however, levels were decreased on aging. OCT3 mRNA expression levels were low in fetal and newborn kidneys, and had two peaks at 35 and 850 days. The selected OAT1 and 3 and MDR1 protein expression levels revealed a similar expression pattern. Thus, kidney transporter expression is affected by ontogeny and aging, which may impact drug and toxicant disposition in children and the elderly.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionsupporting

confidence: 50%

Age-associated differences in transporter gene expression in kidneys of male rats

Wang

et al. 2016

Molecular Medicine Reports

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“…In rodent liver and kidney, several SLC22A/SLCO mRNAs are expressed at a low level and then increase with age, while others are expressed at similar levels in neonatal and adult animals (Sweet et al, ; Klaassen and Aleksunes, ; Hou et al, ; Fattah et al, ). Information on the ontogenesis and regulation of human OAT and OATP transporters is limited.…”

Section: Transcriptional Regulation Of Slc and Slco Genesmentioning

confidence: 99%

Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease

Murray

Zhou

2017

British J Pharmacology

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Organic anion transporters (OATs) and organic anion-transporting polypeptides (OATPs), encoded by a number of solute carrier (SLC)22A and SLC organic anion (SLCO) genes, mediate the absorption and distribution of drugs and other xenobiotics. The regulation of OATs and OATPs is complex, comprising both transcriptional and post-translational mechanisms. Plasma membrane expression is required for cellular substrate influx by OATs/OATPs. Thus, interest in post-translational regulatory processes, including membrane targeting, endocytosis, recycling and degradation of transporter proteins, is increasing because these are critical for plasma membrane expression. After being synthesized, transporters undergo N-glycosylation in the endoplasmic reticulum and Golgi apparatus and are delivered to the plasma membrane by vesicular transport. Their expression at the cell surface is maintained by de novo synthesis and recycling, which occurs after clathrin- and/or caveolin-dependent endocytosis of existing protein. Several studies have shown that phosphorylation by signalling kinases is important for the internalization and recycling processes, although the transporter protein does not appear to be directly phosphorylated. After internalization, transporters that are targeted for degradation undergo ubiquitination, most likely on intracellular loop residues. Epigenetic mechanisms, including methylation of gene regulatory regions and transcription from alternate promoters, are also significant in the regulation of certain SLC22A/SLCO genes. The membrane expression of OATs/OATPs is dysregulated in disease, which affects drug efficacy and detoxification. Several transporters are expressed in the cytoplasmic subcompartment in disease states, which suggests that membrane targeting/internalization/recycling may be impaired. This article focuses on recent developments in OAT and OATP regulation, their dysregulation in disease and the significance for drug therapy.

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“…Cellular sex-based differences have a clear and decisive effect on the possible sex-divergent pharmacokinetics of sunitinib: First, intracellular drug metabolizing enzymes are involved in the biotransformation (Sakuma et al, 2009; Waxman and Holloway, 2009) and generation of active metabolites (e.g., sunitinib’s demethyl metabolite). Second, sex-divergent membrane transporters amount and localization (Cui et al, 2009; Hou et al, 2014; Joseph et al, 2015) may restrict tissue penetration and active excretion processes differently (Bebawy and Chetty, 2009; Franconi and Campesi, 2014b; Mazure, 2016). Furthermore, the study of the effects in both sexes should include studies evaluating the whole lifespan in preclinical animal models, to study the impact of sex hormones at different ages, as they have been linked to clinical outcome differences in humans (Gur and Gur, 2016).…”

Section: Role Of Sex In Future Drug Development Clinical Researchmentioning

confidence: 99%

Sex-Divergent Clinical Outcomes and Precision Medicine: An Important New Role for Institutional Review Boards and Research Ethics Committees

et al. 2017

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The efforts toward individualized medicine have constantly increased in an attempt to improve treatment options. These efforts have led to the development of small molecules which target specific molecular pathways involved in cancer progression. We have reviewed preclinical studies of sunitinib that incorporate sex as a covariate to explore possible sex-based differences in pharmacokinetics and drug–drug interactions (DDI) to attempt a relationship with published clinical outputs. We observed that covariate sex is lacking in most clinical outcome reports and suggest a series of ethic-based proposals to improve research activities and identify relevant different sex outcomes. We propose a deeper integration of preclinical, clinical, and translational research addressing statistical and clinical significance jointly; to embed specific sex-divergent endpoints to evaluate possible gender differences objectively during all stages of research; to pay greater attention to sex-divergent outcomes in polypharmacy scenarios, DDI and bioequivalence studies; the clear reporting of preclinical and clinical findings regarding sex-divergent outcomes; as well as to encourage the active role of scientists and the pharmaceutical industry to foster a new scientific culture through their research programs, practice, and participation in editorial boards and Institutional Ethics Review Boards (IRBs) and Research Ethics Committees (RECs). We establish the IRB/REC as the centerpiece for the implementation of these proposals. We suggest the expansion of its competence to follow up clinical trials to ensure that sex differences are addressed and recognized; to engage in data monitoring committees to improve clinical research cooperation and ethically address those potential clinical outcome differences between male and female patients to analyze their social and clinical implications in research and healthcare policies.

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Age- and sex-related differences of organic anion-transporting polypeptide gene expression in livers of rats

Cited by 30 publications

References 41 publications

Age-associated differences in transporter gene expression in kidneys of male rats

Age-associated differences in transporter gene expression in kidneys of male rats

Trafficking and other regulatory mechanisms for organic anion transporting polypeptides and organic anion transporters that modulate cellular drug and xenobiotic influx and that are dysregulated in disease

Sex-Divergent Clinical Outcomes and Precision Medicine: An Important New Role for Institutional Review Boards and Research Ethics Committees

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