ABCC2
Canalicular multispecific organic anion transporter 1 (ATP-binding cassette sub-family C member 2) (Canalicular multidrug resistance protein) (Multidrug resistance-associated protein 2) (EC 7.6.2.2) [CMOAT] [CMOAT1] [CMRP] [MRP2]
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Human hepatic membrane-embedded transporter proteins are involved in trafficking endogenous and exogenous substrates. Even though impact of transporters on pharmacokinetics is recognized, little is known on maturation of transporter protein expression levels, especially during early life. We aimed to study the protein expression of 10 transporters in liver tissue from fetuses, infants, and adults. Transporter protein expression levels [ATP-binding cassette transporter (ABC)B1, ABCG2, ABCC2, ABCC3, bile salt efflux pump, glucose transporter 1, monocarboxylate transporter 1, organic anion transporter polypeptide (OATP)1B1, OATP2B1, and organic cation/carnitine transporter 2) were quantified using ultraperformance liquid chromatography tandem mass spectrometry in snap-frozen postmortem fetal, infant, and adult liver samples. Protein expression was quantified in isolated crude membrane fractions. The possible association between postnatal and postmenstrual age versus protein expression was studied. We studied 25 liver samples, as follows: 10 fetal [median gestational age 23.2 wk (range 16.4-37.9)], 12 infantile [gestational age at birth 35.1 wk (27.1-41.0), postnatal age 1 wk (0-11.4)], and 3 adult. The relationship of protein expression with age was explored by comparing age groups. Correlating age within the fetal/infant age group suggested four specific protein expression patterns, as follows: stable, low to high, high to low, and low-high-low. The impact of growth and development on human membrane transporter protein expression is transporter-dependent. The suggested age-related differences in transporter protein expression may aid our understanding of normal growth and development, and also may impact the disposition of substrate drugs in neonates and young infants.
MeSH Terms
- ATP-Binding Cassette Transporters
- Adult
- Age Factors
- Aging
- Gestational Age
- Glucose Transporter Type 1
- Humans
- Infant
- Infant, Newborn
- Liver
- Membrane Transport Proteins
- Monocarboxylic Acid Transporters
- Organic Anion Transporters
- Organic Cation Transport Proteins
- Proteomics
- Symporters
The ratio of urinary coproporphyrin (UCP) I to total urinary coproporphyrin I and III [UCP {I/(I III)]] serves as a biomarker of the ATP-binding cassette, sub-family C, member 2 (ABCC2) function. The aim of this study was to clarify the characteristics of the developmental pattern of UCP [I/(I III)] in order to estimate ABCC2 function in children, especially in the neonatal period, by measuring it throughout the entirety of childhood. Measurement of UCP [I/(I III)] was done high-performance liquid chromatography, using urine samples collected from children from 1 day to 15 years old, involving one sample per child. Urine samples from children with liver and kidney disease and urinary tract infection were excluded. UCP [I/(I III)] varied widely in infants younger than 6 months old, and was ≥0.3 in 80% of the infants. In contrast, it decreased to <0.30, the lowest, at 1-2 years old. In the 0-6-month-old group, no significant correlation was noted between postnatal age and UCP [I/(I III)], but a moderate inverse correlation was noted between corrected gestational age and UCP [I/(I III)]. UCP [I/(I III)] is inversely correlated with corrected gestational age and is lowest at 1-2 years old. This suggests that ABCC2 activity is correlated with corrected gestational age and is highest at 1-2 years old.
MeSH Terms
- Adolescent
- Aging
- Biomarkers
- Child
- Child Development
- Child, Preschool
- Chromatography, High Pressure Liquid
- Coproporphyrins
- Female
- Humans
- Infant
- Infant, Newborn
- Male
- Retrospective Studies
Keywords
- ATP-binding cassette, sub-family C, member 2
- bilirubin
- children
- coproporphyrin
- high-performance liquid chromatography
Evaluation of: Fanta S, Niemi M, Jönsson S et al.: Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of ABCB1polymorphisms. Pharmacogenet. Genomics 18(2), 77-90 (2008). The clinical use of the immunosuppressive agent cyclosporine is complicated by its toxicity, narrow therapeutic window and highly variable pharmacokinetics between individuals. In adults, genetic polymorphisms in the genes encoding the cyclosporine-metabolizing enzymes CYP3A4 and CYP3A5, as well as the ABCB1 gene, which encodes the efflux-pump P-glycoprotein, seem to have a limited effect, if any, on cyclosporine pharmacokinetics. However, the authors have now reported for the first time an association between cyclosporine oral bioavailability and the ABCB1 c.1236C>T and c.2677G>T polymorphisms, as well as the related haplotype c.1199G-c.1236C-c.2677G-c.3435C, in children with end-stage renal disease older than 8 years of age. Carriers of the variant alleles had a cyclosporine oral bioavailability that was around 1.5-times higher compared with noncarriers. This association was not observed in children younger than 8 years of age. In addition, no relation between cyclosporine disposition and genetic variation in the CYP3A4, CYP3A5, ABCC2, SLCO1B1 and NR1I2 genes was observed. These data suggest that the effect of ABCB1 polymorphisms on cyclosporine pharmacokinetics is related to age, and thus developmental stage. Although further study is necessary to establish the predictive value of ABCB1 genotyping for individualization of cyclosporine therapy in children older than 8 years, an important step towards further personalized immunosuppressive drug therapy has been made.
MeSH Terms
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Adult
- Aging
- Child
- Cyclosporine
- Humans
- Immunosuppressive Agents
- Inactivation, Metabolic
- Kidney Transplantation
- Pharmacogenetics
- Polymorphism, Single Nucleotide