Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine whether human liver responds to treatment with aromatic hydrocarbons (AHs) with induction of the multidrug resistance (mdr) gene product P-glycoprotein and whether AH induction of mdr involves the Ah receptor, we compared induction of mdr mRNA with induction of cytochrome P450 (CYP)1A1 mRNA in AH-treated cultures of primary human hepatocytes. Hepatocytes from all 15 individuals tested responded to treatment with 3-methylcholanthrene (MC) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with induction of CYP1A1 mRNA. However, only 62% and 55% of the preparations responded to treatment with MC and TCDD, respectively, with induction of mdr mRNA. Indeed, in some individuals mdr mRNA was suppressed by MC and TCDD despite robust CYP1A1 induction. These studies provide the first evidence that not only does individual variation in mdr induction by AH exist but that AHs regulate mdr in humans by a novel mechanism distinguishable from the classical Ah receptor pathway. The dramatic variability in AH induction of mdr may be a predictive risk factor that will help to identify an individual's risk of AH-associated toxicities.
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PMID:Phenotypic variability in induction of P-glycoprotein mRNA by aromatic hydrocarbons in primary human hepatocytes. 766 17

Expression of P-glycoprotein (P-gp), a plasma membrane glycoprotein involved in multidrug resistance and encoded by mdr genes, was investigated in nonparenchymal rat liver epithelial (RLE) cells in response to acute exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs). High levels of mdr mRNAs were evidenced by Northern blotting in two independent RLE cell lines after treatment by either 3-methylcholanthrene (MC) or benzo-(a)pyrene. MC-mediated mdr mRNA induction was demonstrated to be dose-dependent; it occurred through enhanced expression of the mdr 1 gene, as indicated by reverse transcriptase-polymerase chain reaction analysis using rat mdr gene-specific primers and paralleled an induction of a 140 kDa P-gp as demonstrated by Western blotting. In addition, MC-induced P-gp appeared to be fully functional because RLE cells exposed to MC displayed enhanced cellular efflux of rhodamine 123, a known P-gp substrate, compared to their untreated counterparts. Analysis of time-course induction revealed that mdr mRNA levels were maximally increased when RLE cells were treated for 48 to 96 hr and returned to low levels after the PAH was removed. In contrast to P-gp, both cytochrome P-450 1A1 and cytochrome P-450 1A2 were not detected after exposure to MC, thus indicating that these liver detoxification pathways are not coordinately regulated with P-gp in RLE cells. In addition, MC-mediated P-gp regulation was not associated with major cellular disturbances such as alteration of protein synthesis and, thereby, differed from the known mdr mRNA induction occurring in response to cycloheximide. Moreover, cotreatment with MC and cycloheximide led to a superinduction of mdr mRNAs, thus suggesting that the effects of the two xenobiotics were, at least partly, additive. In contrast to MC and benzo(a)pyrene, 2,3,7,8-tetrachlorodibenzo-p-dioxin and benzo(e)pyrene were unable to increase P-gp expression. These results indicate that some PAHs can act as potent inducers of P-gp in RLE cells and may be interpreted as an adaptive reaction of these cells in lowering cellular accumulation of toxic drugs, including carcinogens transported by P-gp and, therefore, conferring protection on these compounds.
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PMID:P-glycoprotein induction in rat liver epithelial cells in response to acute 3-methylcholanthrene treatment. 863 83

The role of protein kinase C and protein phosphatases was examined in the control of mutagenic metabolites of aromatic amines. Various metabolic activating systems derived from rat liver were treated with: 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C modulator; okadaic acid (OA), a potent inhibitor of serine/threonine protein phosphatases (PP1 and PP2A); and ortho-vanadate (OV), an inhibitor of tyrosine phosphatases. TPA used over a wide concentration range (10(-9)-10(-6) M) did not affect the bacterial mutagenicity of the aromatic amines and of the aromatic amide investigated, 2-aminoanthracene, 2-aminofluorene and 2-acetylaminofluorene (2AAF). At the molecular level, TPA did not affect the function of cytochrome P450s 1A1 or 1A2, which are known key factors for the activation and inactivation of aromatic amines/amides. By contrast the OA and OV treatment of rat hepatocytes, rat liver homogenate, fraction S9 and the nuclear fraction drastically reduced (by > 80%) the mutagenicity of the aromatic amines/amide investigated. This is by far the most pronounced change in genotoxicity observed to date via modulation of phosphorylation. Whilst the mutagenicity of the primary toxication product 2-N-OH-acetylaminofluorene (2-N-OH-AAF) in the presence of exogenous activating systems (hepatocytes, S9-fraction, nuclear fraction) was also reduced by OV, OA had no influence. Thus the tyrosine protein phosphatase inhibitor and the serine/threonine protein phosphatase inhibitor influence the genotoxicity of aromatic amines/amides on different levels. Moreover, this shows that the drastic reduction in mutagenicity by OA was due to its influence on a step prior to the presence of the primary toxication product 2-N-OH-AAF. This reduction could be due to changes in the activity of cytochrome P4501A1 and/or 1A2. However, no incorporation of 32P-labelled phosphate from intracellularly prelabelled [32P]-ATP into cytochromes P450 1A1 or 1A2 nor any change in their catalytic activities was observed in the presence of OA. Furthermore, a phosphorylation dependent change in the function of P-glycoprotein (known for its role in the transport of diverse xenobiotic substances and their metabolites) was shown not to contribute to the observed decrease in mutagenicity. Our results reveal an important role for protein phosphatase 1 and/or 2A and tyrosine phosphatase(s) in the control of the genotoxicity of aromatic amines and amides. However, the present study does not distinguish between effects mediated by individual proteins affected by these protein phosphatases.
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PMID:Control of the mutagenicity of aromatic amines by protein kinases and phosphatases. I. The protein phosphatase inhibitors okadaic acid and ortho-vanadate drastically reduce the mutagenicity of aromatic amines. 933 96

Expression of multidrug resistance (mdr) genes encoding the P-glycoprotein (P-gp) drug efflux pump was analysed in cultured rat liver epithelial cells acutely treated by the DNA-damaging agent methyl methanesulfonate (MMS). Exposure to this alkylating agent used at 30 microg/ml for 12 or 24 h was shown to enhance mdr mRNA levels in rat liver cells without alteration of cell viability. Induction of mdr transcripts occurred through increased expression of the mdr1b gene as indicated by reverse transcriptase-polymerase chain reaction analysis using rat mdr gene-specific primers and was not associated with up-regulation of cytochrome P-450 1A1, thereby suggesting that this detoxifying enzyme and P-gp were not coordinately regulated by MMS. In addition, the DNA-damaging agent was found to enhance in a dose-dependent manner cellular efflux of the P-gp substrate rhodamine 123, which was inhibited by the P-gp inhibitor verapamil, thus providing evidence that exposure to MMS led to increased P-gp-related drug transport in rat liver cells. The up-regulation of functional P-gp expression occurring in MMS-treated liver cells may be interpreted as a part of the cellular response to DNA damage.
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PMID:Induction of multidrug resistance gene expression in rat liver cells in response to acute treatment by the DNA-damaging agent methyl methanesulfonate. 953 88

The P-glycoprotein (P-gp)-negative epidermoid pharyngeal carcinoma cells KB-3-1 were grown in 0.25 mM benzo[a]pyrene (BaP) for 3 months and increased resistance to doxorubicin, but not to vinblastine, colchicine, or cisplatin, was found. Doxorubicin resistance was not altered by cyclosporin, the P-gp inhibitor. Intracellular accumulation of BaP or calcein, a substrate for P-gp and multidrug resistance protein (MRP), was not altered by inhibitors of the P-gp and MRP. The expression of cytochrome P450 (CYP) 1A1, lung-resistance-related protein (LRP), P-gp, and MRP was investigated. Overexpression of CYP1A and LRP, on the mRNA and protein levels, was found. BaP-treated KB-3-1 cells remained P-gp negative while the level of MRP was not altered. Subcellular accumulation of BaP was found to be localized in the cytoplasm and minimal in the nuclei in BaP treated cells. In contrast, even penetration of BaP to the nuclei and cytoplasm was found in untreated cells. Subcellular distribution of doxorubicin was altered following BaP treatment with localized accumulation of the cancer drug in cytoplasmic organelles but not in the nuclei. Our data suggested that LRP might play a protective role against toxic compounds. The correlation of increased expression of LRP, but not P-gp nor MRP, with decreased doxorubicin accumulation in the nuclear target suggests a pivotal role of this perinuclear transporter in the MDR phenotype of P-gp-negative cancer cells. These results also propose an alternative mechanism of cancer drug resistance emergence, namely, induction of LRP activity following treatment with BaP, an environmental toxicant and a carcinogen.
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PMID:Low-level doxorubicin resistance in benzo[a]pyrene-treated KB-3-1 cells is associated with increased LRP expression and altered subcellular drug distribution. 1076 26

Human hepatocytes cultured serum-free for up to 6 weeks were used to study expression and induction of enzymes and membrane transport proteins involved in drug metabolism. Phase I drug metabolizing enzymes cytochrome P450 (CYP)1A1, CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4 were detected by Western blot analyses and, when appropriate, by enzymatic assays for ethoxyresorufin-O-deethylase(EROD)-activity and testosterone-6beta-hydroxylase(T6H)-activity. Expression of the membrane transporter multi-drug resistance protein (P-glycoprotein, MDR-1), multidrug resistance-associated protein (MRP-1), and lung-resistance protein (LRP) was maintained during the culture as detected by RT-PCR and Western blot analyses. Model inducers like rifampicin, phenobarbital, or 3-methylcholanthrene and beta-naphtoflavone were able to induce CYP1A or CYP3A4 as well as EROD or T6H activities for up to 30 days. CYP2C9, CYP2C19 and CYP2E1 expression was maintained but not inducible for 48 days. Also, rifampicin and phenobarbital were unable to increase MDR-1 and MRP-1 protein levels significantly.
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PMID:Induction of cytochrome P450 (CYP)1A1, CYP1A2, and CYP3A4 but not of CYP2C9, CYP2C19, multidrug resistance (MDR-1) and multidrug resistance associated protein (MRP-1) by prototypical inducers in human hepatocytes. 1087 7

Cytochrome P450 enzymes metabolize various endogenous and exogenous small molecular weight compounds. Transport-associated proteins, such as P-glycoprotein, multidrug resistance-associated protein and lung resistance protein are overexpressed in drug-resistant cell lines, as well as in human tumors from various histologic origins, including malignant melanoma. Little is known about the expression and function of cytochrome enzymes and multidrug resistance-associated transport proteins in human skin; therefore, the aim of this study was to analyze the expression pattern of cytochrome enzymes and multidrug resistance-associated transport proteins in proliferating human epidermal keratinocytes under constitutive conditions and after induction with various inducers. Reverse transcription-polymerase chain reaction revealed constitutive expression of cytochromes 1A1, 1B1, 2B6, 2E1, and 3A5 in keratinocytes and showed expression of cytochrome 3A4 after incubation with dexamethasone. The expression of cytochrome 1A1 was enhanced on the mRNA level after induction with benzanthracene. Reverse transcription-polymerase chain reaction analysis of the multidrug resistance-associated transport proteins revealed constitutive expression of multidrug resistance-associated proteins 1 and 3-6, and lung resistance protein in human epithelial keratinocytes and was negative for multidrug resistance 1 and 2. Expression of 1 was seen after induction with dexamethasone. Reverse transcription-polymerase chain reaction results were confirmed by immunoblots which showed expression of cytochromes 1A1, 2B6, 2E1, and 3A, multidrug resistance-associated proteins 1, 3, and 5 as well as multidrug resistance 1 after induction with dexamethasone. Immunohistology showed positive immunofluorescence in skin specimens for cytochromes 1A1, 2B6, 2E1, and 3A and multidrug resistance-associated protein 1 and multidrug resistance 1. Constitutive activity of cytochrome 1A1, 2B, 2E1, and 3A enzymes was measured by catalytic assays. These results show that keratinocytes of the human skin express various transport-associated enzymes and detoxifying metabolic enzymes. Previous studies have revealed that cytochrome enzymes and transport-associated proteins play complementary parts in drug disposition by biotransformation (phase I) and anti-transport (phase III) and act synergistically as a drug bioavailability barrier.
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PMID:Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes. 1128 21

Epithelial cells of the gastrointestinal tract are challenged by exposure to many potentially toxic agents including the well-known food contaminant benzo[a]pyrene (B[a]P). They are equipped with a variety of Phase 1- and Phase 2-enzymes that are able to metabolize B[a]P. Furthermore, transmembranous ABC-transport proteins are expressed at the apical pole of these cells. The aim of this study was to investigate whether [14C]B[a]P or products of the metabolism are transported by intestinal cells back into the gut lumen. The intestinal Caco-2 cell line was used as a metabolism and transport model. Experiments with Caco-2 monolayers in the Transwell-system revealed that radiolabeled substance is transported towards the apical (luminal) region. This transport was characterized as active and increased after induction of cytochromes P450 1A1 and 1B1 by beta-naphthoflavone. On the other hand, transport was decreased with the concomitant inhibition of Phase 1-metabolism. TLC-analysis revealed that the primary metabolites of B[a]P found in the supernatant were very polar; other metabolites of less polarity could only be detected in trace amounts. These results indicate that B[a]P is metabolized by Caco-2 cells to highly polar metabolites resulting from biphasic metabolism and that these polar metabolites are subject to an apically directed transport. Chemical inhibition studies showed that P-glycoprotein and MRP1 or 2 were not involved in this polarized B[a]P-metabolite secretion.
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PMID:Human intestinal Caco-2 cells display active transport of benzo[a]pyrene metabolites. 1245 61

Pharmacogenetics focuses on intersubjects variation in therapeutic drug effects and toxicity depending on genetic polymorphisms. This is particularly interesting in oncology since anticancer drugs usually have a narrow margin of safety. Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin] is used in cancer chemotherapy as a topoisomerase I inhibitor and it is characterised by a sometimes unpredictable severe toxicity. It is mostly intestinal with nausea, vomit and diarrhoea or haematologic with leuko-thrombocytopenia. Its complex metabolism involves many proteins. Human carboxylesterase isoforms 1 and 2 (hCE1, hCE2) activate irinotecan to its metabolite SN-38 (7-ethyl-10-hydroxycamptothecin); cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5) mediate the oxidation of the parental compound to irinotecan; uridino-glucuronosil transferase isoform 1A1 (UGT1A1) catalyses glucuronidation of SN-38; the multi-resistance protein isoform 2 (MRP2) allows the cellular excretion of the SN-38 glucuronide (SN-38G) and the multi-drug resistance gene (MDR1), encoding for P-glycoprotein, is responsible for the excretion of irinotecan from the cell. Polymorphic structures in the genes encoding for all these proteins have been described. In particular, the UGT1A1*28 allele has been associated with an increased toxicity after irinotecan chemotherapy. Classical parameters used in the clinic, such as body-surface area, have no longer a meaningful correlation with clinical outcome. Hence it emerges the importance of studying the individual genotype to predict the toxicity and efficacy of irinotecan and to individualise therapy. In this review, we summarise the new developments on the study of the pharmacogenetics of irinotecan, stressing its importance in drug cytotoxic effect.
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PMID:Pharmacogenetics of irinotecan. 1276 80

Hypercholesterolaemia is a risk factor for the development of atherosclerotic disease. Atorvastatin lowers plasma low-density lipoprotein (LDL) cholesterol levels by inhibition of HMG-CoA reductase. The mean dose-response relationship has been shown to be log-linear for atorvastatin, but plasma concentrations of atorvastatin acid and its metabolites do not correlate with LDL-cholesterol reduction at a given dose. The clinical dosage range for atorvastatin is 10-80 mg/day, and it is given in the acid form. Atorvastatin acid is highly soluble and permeable, and the drug is completely absorbed after oral administration. However, atorvastatin acid is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14%. The volume of distribution of atorvastatin acid is 381L, and plasma protein binding exceeds 98%. Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, and the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine. In vitro, atorvastatin acid is a substrate for P-glycoprotein, organic anion-transporting polypeptide (OATP) C and H+-monocarboxylic acid cotransporter. The total plasma clearance of atorvastatin acid is 625 mL/min and the half-life is about 7 hours. The renal route is of minor importance (<1%) for the elimination of atorvastatin acid. In vivo, cytochrome P450 (CYP) 3A4 is responsible for the formation of two active metabolites from the acid and the lactone forms of atorvastatin. Atorvastatin acid and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyltransferases 1A1 and 1A3. Atorvastatin can be given either in the morning or in the evening. Food decreases the absorption rate of atorvastatin acid after oral administration, as indicated by decreased peak concentration and increased time to peak concentration. Women appear to have a slightly lower plasma exposure to atorvastatin for a given dose. Atorvastatin is subject to metabolism by CYP3A4 and cellular membrane transport by OATP C and P-glycoprotein, and drug-drug interactions with potent inhibitors of these systems, such as itraconazole, nelfinavir, ritonavir, cyclosporin, fibrates, erythromycin and grapefruit juice, have been demonstrated. An interaction with gemfibrozil seems to be mediated by inhibition of glucuronidation. A few case studies have reported rhabdomyolysis when the pharmacokinetics of atorvastatin have been affected by interacting drugs. Atorvastatin increases the bioavailability of digoxin, most probably by inhibition of P-glycoprotein, but does not affect the pharmacokinetics of ritonavir, nelfinavir or terfenadine.
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PMID:Clinical pharmacokinetics of atorvastatin. 1453 25


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