Corticosteroid Regulation of P-Glycoprotein in the Developing Blood-Brain Barrier

Iqbal, Majid; Gibb, William; Matthews, Stephen G.

doi:10.1210/en.2010-1227

Cited by 39 publications

(84 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the increased sensitivity to opioids in newborn infants compared to older infants may be attributable, at least in part, to the low expression of P-gp at birth and thereby allowing opioids to concentrate in the CNS. P-gp immunoreactivity was detected in microvessels of the cortex as early as GA 20 wk suggesting that P-gp plays an important role in neuroprotection during fetal brain development, as has previously been shown in animal models (28). Previous studies in the human fetal brain detected P-gp in brain microvessels at crown-rump lengths corresponding to GA 17-24 wk, serving as an early marker of BBB development (26,27,29).…”

Section: Resultssupporting

confidence: 52%

“…Specifically, cyclosporine A accumulation within the brain was the highest in newborn mice and decreased with increasing postnatal P-gp expression (33). A study in guinea pig brain, which has a brain growth pattern that resembles human fetal development, showed that the expression of P-gp protein in the brain microvessels increases with advancing age (28,34). Hence, premature and full-term neonates may be at risk for CNS drug toxicity due to the limited BBB P-gp expression in the brain microvessels.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2015

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 52%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, Demeule et al [38] and Iqbal et al [39] have independently demonstrated that the expression of P-gp is up-regulated by steroids and other hormones whose activity may change during aging. Whether endogenous and/or exogenous (feed) hormones affect ontogenic P-gp expression in chickens needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Age-Related P-Glycoprotein Expression in the Intestine and Affecting the Pharmacokinetics of Orally Administered Enrofloxacin in Broilers

et al. 2013

View full text Add to dashboard Cite

Bioavailability is the most important factor for the efficacy of any drug and it is determined by P- glycoprotein (P-gp) expression. Confirmation of P-gp expression during ontogeny is needed for understanding the differences in therapeutic efficacy of any drug in juvenile and adult animals. In this study, Abcb1 mRNA levels in the liver and intestine of broilers during ontogeny were analysed by RT qPCR. Cellular distribution of P-gp was detected by immunohistochemstry. Age-related differences of enrofloxacin pharmacokinetics were also studied. It was found that broilers aged 4 week-old expressed significantly (P<0.01) higher levels of P-gp mRNA in the liver, jejunum and ileum, than at other ages. However, there was no significant (P>0.05) age-related difference in the duodenum. Furthermore, the highest and lowest levels of Abcb1 mRNA expression were observed in the jejunum, and duodenum, respectively. P-gp immunoreactivity was detected on the apical surface of the enterocytes and in the bile canalicular membranes of the hepatocytes. Pharmacokinetic analysis revealed that the 8 week-old broilers, when orally administrated enrofloxacin, exhibited significantly higher Cmax (1.97 vs. 0.98 μg•ml-1, P=0.009), AUC(14.54 vs. 9.35 μg•ml-1•h, P=0.005) and Ka (1.38 vs. 0.43 h-1, P=0.032), as well as lower Tpeak (1.78 vs. 3.28 h, P=0.048) and T1/2ka (0.6 vs. 1.64 h, P=0.012) than the 4 week-old broilers. The bioavailability of enrofloxacin in 8 week-old broilers was increased by 15.9%, compared with that in 4 week-old birds. Interestingly, combining verapamil, a P-gp modulator, significantly improved pharmacokinetic behaviour of enrofloxacin in all birds. The results indicate juvenile broilers had a higher expression of P-gp in the intestine, affecting the pharmacokinetics and reducing the bioavailability of oral enrofloxacin in broilers. On the basis of our results, it is recommended that alternative dose regimes are necessary for different ages of broilers for effective therapy.

show abstract

“…One possible reason for such variability is that the ABCB1 gene is polymorphic, and two of its single-nucleotide polymorphisms (SNPs), rs1128503 and rs1045642, may modify the final protein conformation, compromising its membrane stability and substrate recognition 7,8. Finally, it has been reported that the ABCB1 expression may also be modulated by plasma aldosterone9 or cortisol,10 as well as by dietary salt and dehydration 9…”

Section: Introductionmentioning

confidence: 99%

Loss of constitutive <em>ABCB1</em> expression in breast cancer associated with worse prognosis

Delou¹,

Vignal²,

Indio-do-Brasil³

et al. 2017

BCTT

View full text Add to dashboard Cite

ABCB1 gene encodes an adenosine 5′-triphosphate–binding cassette transporter, which not only confers multidrug resistance phenotype in malignant cells, but is also present in several nonmalignant tissues. For the last thirty years, ABCB1 expression in breast cancer has been described by many authors, but the extent of expression differs among the studies, and there is no consensus regarding its potential role in carcinogenesis or in the tumor response to antineoplastic drugs. This study aimed to characterize the expression of ABCB1 in breast tumors as a function of genetic, clinical, and histopathological variables. The ABCB1 expression was also evaluated in nonmalignant mammary tissues adjacent to tumors and in benign lesions. The detection of ABCB1 protein was performed by immunohistochemistry in tissue specimens of excised breasts obtained from a prospective cohort of Brazilian women with breast cancer. The association of ABCB1 protein levels with ABCB1 mRNA, gene polymorphisms, and clinical and histopathological variables was also evaluated. The Kaplan–Meier curves and multivariate Cox regression analyses were conducted to identify independent predictors of disease-free survival of patients with breast cancer. ABCB1 was detected in 86.3% (656) of breast tumors, 98.8% (606) of nonmalignant mammary tissue adjacent to tumors, and 100% (28) of benign lesions. Reduced ABCB1 protein levels in breast tumors was associated with triple-negative subtype (adjusted odds ratio [ORadj] =0.24; 95% confidence interval [CI] =0.13–0.45), lymph node status < pN2 (ORadj =0.27; 95% CI =0.10–0.71), tumor size >2 cm (ORadj =0.55; 95% CI =0.32–0.93), and hypertensive status (ORadj =0.42; 95% CI =0.24–0.73), and it was significantly associated with shorter disease-free survival, either for all breast cancer patients (p log-rank =0.012; hazard ratio [HR] =3.46; 95% CI =1.21–9.91) or for those with triple-negative tumors (p log-rank =0.007; HR =11.41; 95% CI =1.29–100.67). The loss of constitutive ABCB1 expression in breast cancer, especially in triple-negative tumors, seems to indicate a subgroup of worse prognosis.

show abstract

Corticosteroid Regulation of P-Glycoprotein in the Developing Blood-Brain Barrier

Cited by 39 publications

References 54 publications

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

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

Age-Related P-Glycoprotein Expression in the Intestine and Affecting the Pharmacokinetics of Orally Administered Enrofloxacin in Broilers

Loss of constitutive <em>ABCB1</em> expression in breast cancer associated with worse prognosis

Contact Info

Product

Resources

About