Effect of the mutation (C3435T) at exon 26 of the <i>MDR1</i> gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects

Nakamura, Tsutomu; Sakaeda, Toshiyuki; Horinouchi, Masanori; Tamura, Takao; Aoyama, Nobuo; Shirakawa, Toshiro; Matsuo, Masafumi; Kasuga, Masato; Okumura, Katsuhiko

doi:10.1067/mcp.2002.122055

Cited by 245 publications

(162 citation statements)

References 17 publications

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“…A similar tendency was observed before in myocardial tissue 35 and in the intestine of Japanese subjects. 36 Overall ratios from mRNA/18S rRNA did not correlate with protein content neither in noncancerous nor in cancerous tissue. However, translation efficiency and membrane trafficking is not necessarily proportional to mRNA transcription efficiency 37 and the estimated half-time of P-gp is reportedly 3.7 days, 38 but the mRNA stability was shown to be much shorter.…”

Section: Discussionmentioning

confidence: 99%

Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

et al. 2006

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There is increasing evidence that polymorphisms of the adenosine 5 0 triphosphate membrane transporters ABCB1 (P-glycoprotein, MDR1) may affect expression and function, whereas less information is available about the impact of ABCC2 (multidrug resistance-associated protein (MRP2)) single-nucleotide polymorphisms . Particularly, their role in human kidney for drug elimination and in the etiology of renal cell carcinoma is poorly understood. ABCB1 and ABCC2 mRNA and protein expression levels were determined by real-time polymerase chain reaction or immunohistochemistry in kidney cancer and adjacent unaffected cortex tissue of 82 nephrectomized renal cell cancer (RCC) patients (63 clear-cell RCC (CCRCC), 19 non-CCRCC). The DNA of all patients was genotyped for ABCB1 À2352G4A, À692T4C, 2677G4T/A (Ala893Ser/Thr), and 3435C4T, and ABCC2 À24C4T, 1249G4A (Val417Ile) and 3972C4T. ABCB1 and ABCC2 were less expressed in CCRCC than in normal cortex on mRNA as well as on protein level. Although the overall genotype frequency distribution did not differ between the patients and a matched control group, ABCB1 2677T/ A and 3435T genotypes were associated with higher (P ¼ 0.02 and P ¼ 0.04) and ABCC2 À24 T with lower mRNA levels in normal tissues (0.03). The expression of ABCB1 and ABCC2 was not related to genetic variants in RCC tissue. In a reporter gene assay in HepG2 cells, the ABCC2 À24T construct showed an 18.7% reduced activity (P ¼ 0.003). In conclusion, ABCB1 and ABCC2 genotypes modulate the expression in the unaffected renal cortex of RCC patients, possibly contributing to inter-individual differences in drug and xenobiotics elimination. Their role in RCC cancer susceptibility or chemotherapy resistance needs further elucidation.

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Section: Discussionmentioning

confidence: 99%

Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

et al. 2006

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“…Future studies should investigate the ontogeny of P-gp in other brain regions and astrocytes. Moreover, genetic polymorphisms, which were not assessed in this cohort, have been shown to alter P-gp expression (36,37). Future studies should address the impact of genetic polymorphisms on P-gp-medicated drug transport in newborns.…”

Section: Resultsmentioning

confidence: 99%

The ontogeny of P-glycoprotein in the developing human blood–brain barrier: implication for opioid toxicity in neonates

et al. 2015

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Background:Neonates have been shown to have a heightened sensitivity to the central depressive effects of opioids compared to older infants and adults. The limited development of P-glycoprotein (P-gp) may limit the ability of the neonate to efflux morphine from the brain back to the systemic circulation. The objective of the study was to determine the ontogeny of P-gp in the human brain. Methods: Postmortem cortex samples from gestational age (GA) 20-26 wk, GA 36-40 wk, postnatal age (PNA) 0-3 mo, PNA 3-6 mo, and adults were immunostained for P-gp. results: The intensity of P-gp staining in adults was significantly higher compared to at GA 20-26 wk (P < 0.05), GA 36-40 wk (P < 0.05), and PNA 0-3 mo (P < 0.05). P-gp intensity at GA 20-26 wk (P < 0.05), GA 36-40 wk (P < 0.05), and PNA 0-3 mo (P < 0.05) was significantly lower compared to at PNA 3-6 mo. conclusion: P-gp expression in the brain is limited at birth, increases with postnatal maturation, and reaches adult levels at ~3-6 mo of age. Given the immaturity of blood-brain barrier (BBB) P-gp after birth, morphine may concentrate in the brain. This provides mechanistic support to life threatening opioid toxicity seen with maternal codeine use during breastfeeding.

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“…18 Two studies have described the opposite association, that is, the T polymorphism associated with increased mRNA expression, but once again these have been either nonsignificant 19 or performed on a very small sample. 20 The majority have failed to find an association, 17,[21][22][23][24][25] although two of these negative studies did show an association with haplotype rather than genotype. 17,21 Most studies of the 2677G4TA polymorphism and mRNA expression levels have also been negative, 17,19,21,[23][24][25] although one study 22 did report an association between the GG2677 genotype and reduced mRNA expression.…”

Section: Effects Of Genotype On Abcb1 Mrna and Protein Expressionmentioning

confidence: 99%

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

et al. 2006

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The product of the ABCB1 gene, P-glycoprotein (PGP), is a transmembrane active efflux pump for a variety of drugs. It is a putative mechanism of multidrug resistance in a range of diseases. It is postulated that ABCB1 polymorphisms contribute to variability in PGP function, and that therefore multidrug resistance is, at least in part, genetically determined. However, studies of ABCB1 genotype or haplotype and PGP expression, activity or drug response have produced inconsistent results. This critical review of ABCB1 genotype and PGP function, including mRNA expression, PGP-substrate drug pharmacokinetics and drug response, highlights methodological limitations of existing studies, including inadequate power, potential confounding by co-morbidity and co-medication, multiple testing, poor definition of disease phenotype and outcomes, and analysis of multiple drugs that might not be PGP substrates. We have produced recommendations for future research that will aid clarification of the association between ABCB1 genotypes and factors related to PGP activity.

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Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects

Cited by 245 publications

References 17 publications

Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

The ontogeny of P-glycoprotein in the developing human blood–brain barrier: implication for opioid toxicity in neonates

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

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