Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Etoposide is a substrate for P-glycoprotein, CYP3A4, CYP3A5, and UGT1A1. Glucocorticoids modulate CYP3A and P-glycoprotein in preclinical models, but their effect on clinical etoposide disposition is unknown. We studied the pharmacokinetics of etoposide and its catechol metabolite in children with acute lymphoblastic leukemia, along with polymorphisms in CYP3A4, CYP3A5, MDR1, GSTP1, UGT1A1, and VDR. Plasma pharmacokinetics were assessed at day 29, after 1 month of prednisone (n = 102), and at week 54, without prednisone (n = 44). On day 29, etoposide clearance was higher (47.4 versus 29.2 mL/min/m2, P <.0001) than at week 54. The day 29 etoposide or catechol area under the curve (AUC) was correlated with neutropenia (P =.027 and P =.0008, respectively). The relationship between genotype and etoposide disposition differed by race and by prednisone use. The MDR1 exon 26 CC genotype predicted higher day 29 etoposide clearance (P =.002) for all patients, and the CYP3A5 AA and GSTP1 AA genotypes predicted lower clearance in blacks (P =.02 and.03, respectively). The UGT1A1 6/6, VDR intron 8 GG, and VDR Fok 1 CC genotypes predicted higher week 54 clearance in blacks (P =.039,.036, and.052, respectively). The UGT1A1 6/6 genotype predicted lower catechol AUC. Prednisone strongly induces etoposide clearance, genetic polymorphisms may predict the constitutive and induced clearance of etoposide, and the relationship between genotype and phenotype differs by race.
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PMID:Effects of prednisone and genetic polymorphisms on etoposide disposition in children with acute lymphoblastic leukemia. 1296 65

ABCB1 (P-glycoprotein) is an efflux transporter that limits the cellular uptake levels of various drugs in intestine, brain, and other tissues. The expression of human ABCB1 has recently been reported to be under the control of nuclear receptor NR1I subfamily members, pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3). Here, we have investigated the involvement of another NR1I member, vitamin D receptor (VDR, NR1I1), in ABCB1 expression. In the human colorectal adenocarcinoma cell line LS174T, which abundantly expresses VDR, both 1alpha,25-dihydroxyvitamin D(3) (1,25-VD3) and lithocholic acid (LCA) increased ABCB1 mRNA levels. Reporter gene assays in LS174T cells with constructs containing various lengths of the ABCB1 regulatory region revealed that the region containing multiple nuclear receptor binding motifs located at -7.8 kilobases [termed nuclear receptor-responsive module (NURREM)], to which PXR and CAR also bind, is essential for the VDR-mediated ABCB1 transactivation. Further reporter assays with constructs containing truncated NURREM and gel shift assays suggested simultaneous binding of multiple VDR/retinoid X receptor alpha heterodimers to NURREM. Furthermore, knockdown of VDR expression in LS174T cells blocked the LCA- and the 1,25-VD3-induced transcription of ABCB1 reporter genes. In human hepatoma HepG2 cells, in contrast with LS174T cells, 1,25-VD3 activated the ABCB1 transcription only in the presence of ectopically expressed VDR. These results suggest that the NR1I subfamily members regulate the ABCB1 expression sharing the binding sites within NURREM and that the physiologically produced LCA and 1,25-VD3 may modulate the ABCB1 expression in human intestines, possibly associated with interindividual variations of ABCB1 expression.
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PMID:Involvement of Vitamin D receptor in the intestinal induction of human ABCB1. 1946 Sep 46

Over the past 20 years, the toxicological and protective roles of the placental barrier with respect to drug detoxification and transporter-controlled protection of the fetus have been intensively examined. Several cytochrome P450 enzymes are expressed in placental trophoblast at different stages of pregnancy, though only a few of these have functional activity to metabolize xenobiotics. Drug transporters such as P-glycoprotein/MDR1 or breast cancer resistance protein (BCRP) are highly expressed in the placenta, and their functional activities have been demonstrated in the placenta both in vitro and in vivo. In addition, several studies have reported on ligand-activated transcription factors and nuclear receptors referred to as "xenosensors" in the placenta. The xenosensors control transcriptional regulation of both xenobiotic-metabolizing enzymes and drug transporters in different organs. Their ligands include toxic compounds and environmental pollutants, drugs, as well as herbal, dietary or vitamin supplements. Nevertheless, it remains debatable whether the placental barrier adapts to toxic injuries coming either from maternal medication or environmental contamination and whether the placenta contains a mechanism to respond dynamically in protecting the developing fetus. In the present paper, we summarize current knowledge about the activity and expression of major ligand-activated transcriptional mechanisms involved in biotransformation enzymes and transporters regulation in human placenta. In particular, we highlight the emerging roles of aryl hydrocarbon (AHR), vitamin D (VDR), glucocorticoid (GR) and pregnane X (PXR) receptors in that regulation. We show that the placenta constitute a unique metabolizing organ with significant overlap of exogenous and endogenous compounds metabolism controlled by nuclear receptors.
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PMID:Nuclear receptors in regulation of biotransformation enzymes and drug transporters in the placental barrier. 2402 Mar 84