Proteomic Analysis of the Developmental Trajectory of Human Hepatic Membrane Transporter Proteins in the First Three Months of Life

Mooij, Miriam G.; Steeg, Evita van de; Rosmalen, Joost van; Windster, Jonathan D; Koning, Barbara A E de; Vaes, Wouter H. J.; Groen, Bianca D van; Tibboel, Dick; Wortelboer, Heleen M.; Wildt, Saskia N. de

doi:10.1124/dmd.115.068577

Cited by 37 publications

(33 citation statements)

References 42 publications

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“…P‐gp expression levels in the liver only reached 50% of adult expression levels at 2.9 years of age, whereas our results suggested that full adult levels were achieved in the kidneys by that age. For BCRP, our results for mRNA expression in the kidneys were consistent with that in the liver, which showed a decline from newborns to adults . As more transporter ontogenetic data in different organs become available, more reliable prediction in transporter‐mediated substrate disposition on the whole‐body level during development will be achieved.…”

Section: Discussionsupporting

confidence: 75%

A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

Cheung

Groen

Spaans

et al. 2019

Clin Pharma and Therapeutics

136

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Human renal membrane transporters play key roles in the disposition of renally cleared drugs and endogenous substrates, but their ontogeny is largely unknown. Using 184 human postmortem frozen renal cortical tissues (preterm newborns to adults) and a subset of 62 tissue samples, we measured the mRNA levels of 11 renal transporters and the transcription factor pregnane X receptor (PXR) with quantitative real-time polymerase chain reaction, and protein abundance of nine transporters using liquid chromatography tandem mass spectrometry selective reaction monitoring, respectively. Expression levels of p-glycoprotein, urate transporter 1, organic anion transporter 1, organic anion transporter 3, and organic cation transporter 2 increased with age. Protein levels of multidrug and toxin extrusion transporter 2-K and breast cancer resistance protein showed no difference from newborns to adults, despite age-related changes in mRNA expression. Multidrug and toxin extrusion transporter 1, glucose transporter 2, multidrug resistance-associated protein 2, multidrug resistance-associated protein 4 (MRP4), and PXR expression levels were stable. Using immunohistochemistry, we found that MRP4 localization in pediatric samples was similar to that in adult samples. Collectively, our study revealed that renal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of substrates may change with age.

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Section: Discussionsupporting

confidence: 75%

A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

Cheung

Groen

Spaans

et al. 2019

Clin Pharma and Therapeutics

136

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“…Moreover, most of these human transporter mRNA expression data are limited to fetal livers . Proteomics quantification of 10 drug transporters (excluding OCT1 and OATP1B3) in human livers has recently been reported . However, because this study was primarily based on the limited number of fetal and infant samples, the developmental patterns are not conclusive.…”

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confidence: 97%

Ontogeny of Hepatic Drug Transporters as Quantified by LC‐MS/MS Proteomics

Prasad

Gaedigk

Vrana

et al. 2016

Clin Pharma and Therapeutics

123

179

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Protein expression of major hepatic uptake and efflux drug transporters in human pediatric (n=69) and adult (n=41) livers was quantified by LC-MS/MS. Transporter protein expression of OCT1, OATP1B3, P-gp and MRP3 was age-dependent. Particularly, significant differences were observed in transporter expression (p <0.05) between the following age-groups: neonates vs. adults (OCT1, OATP1B3, P-gp), neonates or infants vs. adolescents and/or adults (OCT1, OATP1B3 and P-gp), infants vs. children (OATP1B3 and P-gp) and adolescents vs. adults (MRP3). OCT1 showed the largest increase, of almost 5-fold, in protein expression with age. Ontogenic expression of OATP1B1 was confounded by genotype and was revealed only in livers harboring SLCO1B1*1A/*1A. In livers > 1 year, tissues harboring SLCO1B1*14/*1A showed 2.5-fold higher (P<0.05) protein expression than SLCO1B1*15/*1A. Integration of these ontogeny data in physiologically based pharmacokinetic (PBPK) models will be a crucial step in predicting hepatic drug disposition in children.

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“…Findings of studies on the developmental pattern of the ABCC3 transporter during childhood are inconsistent. Based on the proteomic study that did illustrate a "low to high" developmental pattern, adult protein expression values are reached within the first 5 postnatal weeks (40 ). Therefore, it would be worthwhile to assess if the reported effect of the Ϫ211CϾT variant on morphine PK could also be found in the neonatal population.…”

Section: Abcc3mentioning

confidence: 99%

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

et al. 2017

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BACKGROUND The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics (PGx) could possibly be used to tailor pain medication based on an individual's genetic background. Many potential genetic markers have been described, and the importance of genetic predisposition in opioid efficacy and toxicity has been demonstrated in knockout mouse models and human twin studies. Such predictors are especially of value for neonates and young children, in whom the assessment of efficacy or side effects is complicated by the inability of the patient to communicate this properly. The current problem is determining which of the many potential candidates to focus on for clinical implementation. CONTENT We systematically searched publications on PGx for opioids in 5 databases, aiming to identify PGx markers with sufficient robust data and high enough occurrence for potential clinical application. The initial search yielded 4257 unique citations, eventually resulting in 852 relevant articles covering 24 genes. From these genes, we evaluated the evidence and selected the most promising 10 markers: cytochrome P450 family 2 subfamily D member 6 (CYP2D6), cytochrome P450 family 3 subfamily A member 4 (CYP3A4), cytochrome P450 family 3 subfamily A member 5 (CYP3A5), UDP glucuronosyltransferase family 2 member B7 (UGT2B7), ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C member 3 (ABCC3), solute carrier family 22 member 1 (SLC22A1), opioid receptor kappa 1 (OPRM1), catechol-O-methyltransferase (COMT), and potassium voltage-gated channel subfamily J member 6 (KCNJ6). Treatment guidelines based on genotype are already available only for CYP2D6. SUMMARY The application of PGx in the management of pain with opioids has the potential to improve therapy. We provide a shortlist of 10 genes that are the most promising markers for clinical use in this context.

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Proteomic Analysis of the Developmental Trajectory of Human Hepatic Membrane Transporter Proteins in the First Three Months of Life

Cited by 37 publications

References 42 publications

A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

Ontogeny of Hepatic Drug Transporters as Quantified by LC‐MS/MS Proteomics

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

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