Open AccessJournal Article
Multidrug resistance gene (P-glycoprotein) expression in the human fetus.
C.K. van Kalken,Giuseppe Giaccone,P. van der Valk,C. M. Kuiper,M. M. N. Hadisaputro,A.A. Bosma,R.J. Scheper,C. J. L. M. Meijer,H.M. Pinedo +8 more
TLDR
A pivotal role of P-glycoprotein in physiology of various organs already in early phases of human development is suggested and may help to identify its physiologic substrates.Abstract:
P-glycoprotein, a transmembrane protein associated with multidrug resistance in cancer cells, is also expressed in normal tissues. To get more insight into the physiologic role of mdr1/P-glycoprotein, we investigated its expression in human fetal tissues after 7 to 38 weeks of gestation by an immunohistochemical technique, using three different monoclonal antibodies, and by a sensitive RNAse protection assay. Expression of mdr1-mRNA could already be demonstrated in the embryonal phase of human development, after 7 weeks of gestation. Comparing the adult with the fetal tissue distribution, differences were found in specific organs, such as adrenal, intestine, respiratory epithelium, and brain capillaries. In the fetal zone cells of the fetal adrenal cortex no staining was observed by immunohistochemistry, whereas the definitive zone showed increasing expression throughout gestation. Prenatal intestine did not show staining of the epithelium, although definite mdr1-mRNA expression was observed in late specimens. Interestingly, respiratory epithelium of main bronchi and pharynx, not expressing P-gp in adults, did stain positive. Expression of P-gp in brain capillaries was not observed before the third trimester of pregnancy, whereas in kidney and liver, mdr1-mRNA expression and staining for P-glycoprotein were detected in early fetal life (11 to 14 weeks). These findings suggest a pivotal role of P-glycoprotein in physiology of various organs already in early phases of human development and may help to identify its physiologic substrates.read more
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Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children.
Trevor N. Johnson,Amin Rostami-Hodjegan,Amin Rostami-Hodjegan,Geoffrey T. Tucker,Geoffrey T. Tucker +4 more
TL;DR: The in silico prediction of pharmacokinetic behaviour in paediatric patients is not intended to replace clinical studies, however, it provides a valuable aid to decision-making with regard to first-time dosing in children and study design.
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Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure
TL;DR: The findings imply that the placental drug-transporting P-gp is of great importance in limiting the fetal penetration of various potentially harmful or therapeutic compounds and demonstrate that this P- gp function can be abolished by pharmacological means.
Journal ArticleDOI
Multiple physiological functions for multidrug transporter P-glycoprotein?
TL;DR: This work has raised the possibility that P-gp and related transporter molecules might play a fundamental role in regulating cell differentiation, proliferation and survival in multicellular organisms.
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Ontogeny of Hepatic and Renal Systemic Clearance Pathways in Infants Part I
Jane Alcorn,Patrick J. McNamara +1 more
TL;DR: The summary of the current understanding of the ontogeny of individual pathways of hepatic and renal elimination presented in this review should serve as a basis for the continued accruement of age-specific information concerning the ontogenicy of clearance mechanisms in infants.
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Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit.
Hitoshi Ishimoto,Robert B. Jaffe +1 more
TL;DR: Mounting evidence indicates that actions of hormones operating in the human feto-placental unit are likely mediated by mechanisms including target tissue responsiveness, local metabolism, and bioavailability, rather than changes only in circulating levels.
References
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Journal ArticleDOI
Identification of two distinct regulatory regions adjacent to the human β-interferon gene
TL;DR: To study the regulation of the human beta-interferon (beta-IFN) gene by poly(I)-poly(C), the expression of deletion mutants of the cloned gene introduced into mouse cells on a new bovine papilloma virus vector is analyzed.
Journal ArticleDOI
Isolation and expression of a complementary DNA that confers multidrug resistance.
TL;DR: The isolation of DNA clones complementary to the cellular messenger RNA transcripts of mdr genes are reported and it is shown that high-level expression of a full-length complementary DNA clone in an otherwise drug-sensitive cell confers a complete multidrug-resistant phenotype.
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P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins.
TL;DR: It now appears that Pgp‐mediated MDR tumor cells do occur in human cancers, and that they are likely to play a role in the ultimate response of patients to chemotherapy.