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)

Myopathy is usually a non-fatal muscle disease involving skeletal muscle weakness, tenderness and pain with the possibility of the plasma creatinine kinase elevation. There are many different types of myopathies, some of which are genetic, inflammatory, or related to endocrine dysfunction. Also, numerous drugs have been reported to possess myotoxic effect. Myopathy is included among the potential side-effects and toxicities associated with the lipid lowering agents, particularly 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. However, the precise mechanism of statin-induced muscle toxicity remains unclear. The muscle-related side-effects reported with lipid-lowering drugs are significant but quite rare (0.1%), when used in monotherapy; while the incidence of steroid-induced myopathy has varied from 7 to 60%% and chronic alcoholic myopathy seems to be common complication of alcoholism affecting approximately 50% of patients, respectively. This review focuses on the differential pathophysiological grounds of these muscular injuries induced by statins, fibrates, as well as some other agents: corticosteroids or alcohol. A wide spectrum of possible mechanisms and hypotheses including muscle enzyme defects, changes in mitochondrial function and intracellular metabolism, the influence on the cell membrane stability and drug interactions involving P-glycoprotein or cytochrome P 450 system have been presented.
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PMID:Drug-induced myopathies. An overview of the possible mechanisms. 1584 74

Organ transplantation has become an important additional option for patients with organ failure. Immunosuppressive drugs showing a very narrow therapeutic window have to be administered. Different transporters and metabolic pathways are responsible for absorption and metabolism of these drugs; for instance, the P-glycoprotein (P-gp) pump regulates the absorption of a drug, and its metabolism is catalyzed by cytochrome P450s (CYPs). As the phenotypes of P-gp or the CYPs are predetermined by their genotypes, genetic testing prior to drug therapy may help to predict the drug doses required. This review describes polymorphisms of the genes coding for P-gp and CYPs, and focuses on the compounds cyclosporin and tacrolimus. It is hoped that this information might help to judge the value of pharmacogenetic testing prior to immunosuppressive therapy in solid organ transplantation.
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PMID:Clinical pharmacogenetics of immunosuppressive drugs in organ transplantation. 1588 34

Following the negative experience with thalidomide, women were excluded from participation in clinical trials with new pharmaceutical agents as far as possible, especially from phase I studies. However, in the early 1990s a body of evidence accumulated suggesting clinically relevant gender-related differences in the efficacy and safety of drugs. Gender-related differences have been shown for the metabolism and the effects of drugs. Gender differences have been described especially for the enzymes of the cytochrome P 450 family, but also for phase II reactions and most recently for P-glycoprotein. Most of these differences observed are only of minor clinical relevance, however may result in an increased rate of adverse drug reactions. Further differences may be based on different receptor/target sensitivities, e. g. the increased sensitivity for drug-induced torsade de pointes arrhythmia in women. In addition, in complex diseases such as heart failure, men and women may develop different mechanisms of counter- regulation requiring different therapeutic approaches. Population-based approaches demonstrate gender differences in the incidence of adverse drug reactions.
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PMID:[Gender-related differences in pharmacokinetics and pharmacodynamics]. 1588 63

Man is permanently exposed to exogenous substances, either natural ones (e.g. mycotoxins, plant extracts) or man-made compounds such as pesticides or drugs. In some cases, such foreign compounds can exert either therapeutic (drugs) or toxic effects, or both. In particular, fungi are the source of a number of different secondary metabolites having such therapeutic or toxic effects. The efficiency or toxicity of foreign compounds depends on their ability to cross the cytoplasmic membrane. The exogenous molecules subsequently bind to their specific receptor in the cytoplasm or nucleus of the cell, but they are also attacked by the detoxification proteins, which in mammals are mainly composed of two types of membrane enzyme systems: cytochrome P450s, which functionalize hydrophobic xenobiotics, and an active P-glycoprotein (P-gp) transport system involved in the efflux of xenobiotics. These processes are illustrated through the use of two fungal cyclopeptides, cyclosporin A (CsA) and roquefortine C. The former, CsA, is known to be an immunosuppressor, while the latter, roquefortine C, is a potentially neurotoxic compound. CsA inhibits P-gp in a different way from its metabolites, whereas roquefortine C activates P-gp and also inhibits P450-3A and other haemoproteins. The current observations show that the two detoxification systems complement each other, resulting in a given toxicity level. The two mammal enzyme systems might therefore prove useful in the development of toxicity screening procedures.
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PMID:Oxidative metabolism by P450 and function coupling to efflux systems: modulation of mycotoxin toxicity. 1601 6

Indole-3-carbinol (I3C) is produced by members of the family Cruciferae, and particularly members of the genus Brassica (e.g., cabbage, radishes, cauliflower, broccoli, Brussels sprouts, and daikon). Under acidic conditions, 13C is converted to a series of oligomeric products (among which 3,3'-diindolylmethane is a major component) thought to be responsible for its biological effects in vivo. In vitro, 13C has been shown to suppress the proliferation of various tumor cells including breast cancer, prostate cancer, endometrial cancer, colon cancer, and leukemic cells; induce G1/S arrest of the cell cycle, and induce apoptosis. The cell cycle arrest involves downregulation of cyclin D1, cyclin E, cyclin- dependent kinase (CDK)2, CDK4, and CDK6 and upregulation of p15, p21, and p27. Apoptosis by I3C involves downregulation antiapoptotic gene products, including Bcl-2, Bcl-xL, survivin, inhibitor-of-apoptosis protein (IAP), X chromosome-linked IAP (XIAP), and Fas-associated death domain protein-like interleukin-1-beta-converting enzyme inhibitory protein (FLIP); upregulation of proapoptotic protein Bax; release of micochondrial cytochrome C; and activation of caspase-9 and caspase-3. This agent inhibits the activation of various transcription factors including nuclear factor-kappaB, SP1, estrogen receptor, androgen receptor and nuclear factor-E2-related factor 2 (Nrf2). This indole potentiates the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through induction of death receptors and synergises with chemotherapeutic agents through downregulation of P-glycoprotein (P-gp). In vivo, I3C was found to be a potent chemopreventive agent for hormonal-dependent cancers such as breast and cervical cancer. These effects are mediated through its ability to induce apoptosis, inhibit DNA-carcinogen adduct formation, and suppress free-radical production, stimulate 2-hydroxylation of estradiol, inhibit invasion and angiogenesis. Numerous studies have indicated that I3C also has a strong hepatoprotective activity against various carcinogens. Initial clinical trials in women have shown that I3C is a promising agent against breast and cervical cancers.
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PMID:Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. 1608 11

The recent development of new antiretroviral drugs, along with the evolution in clinical practice guidelines that include the recommendation of the use of three- to four-drug combination regimens for achieving optimal suppression of viral replication, has focused clinicians on the relevance of drug-drug interactions in the chronic care of HIV-infected individuals. However, the routine clinical management of drug interactions is complicated by our expanding knowledge of the physiologic mechanisms underlying pharmacokinetic interactions, particularly as they relate to drug transport and tissue distribution (eg, P-glycoprotein) and biotransformation (hepatic cytochrome p450 mono-oxygenase induction and inhibition). This review provides an updated summary of key drug interactions that have been reported since its initial publication.
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PMID:Drug interactions with antiretrovirals. 1609 Dec 28

Two cases with QT prolongation associated with the administration of standard drug doses are reported. Drug effects are determined by pharmacological and biological parameters. Drugs may be metabolized or transported by two systems: the cytochrome enzymes or the less well-known but nevertheless relevant P-glycoprotein system. P-glycoprotein is a pump that limits intracellular reabsorption and favors the elimination of exogenous substances. These two systems interact with each other to influence drug effects. A better knowledge of their mechanisms of action and their genetic determinants should help provide more individualized pharmacologic treatment to patients, in particular older patients.
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PMID:[QT prolongation and inhibition of the P glycoprotein: presentation of 2 geriatric cases]. 1632 34

This review focuses on drug-drug interactions with three major groups of antimicrobial agents: macrolides (including azalides and ketolides), quinolones, which are widely used for the treatment of bacterial infections, and azoles, which are used for antifungal therapy. Macrolides and the ketolide telithromycin are potent inhibitors of CYP3A4 and thus interfere with the pharmacokinetics of many other drugs that are metabolised by this enzyme. In contrast, although closely related, azithromycin is not a cytochrome inhibitor. All quinolones form complexes with di- and trivalent cations and, therefore, the absorption of quinolones can be dramatically reduced when given concomitantly with mineral antacids, zinc or iron preparations. Ciprofloxacin exhibits an inhibitory potential for the cytochrome isoenzyme 1A2, resulting in an inhibition of theophylline metabolism. Other quinolones, such as levofloxacin or moxifloxacin, do not interfere with theophylline metabolism. The systemic azoles, such as ketoconazole, itraconazole, fluconazole and voriconazole, are inhibitors of CYP isoenzymes, such as CYP3A4, CYP2C9 and CYP2C19, to varying degrees. In addition, some are substrates of the MDR-1 gene product, P-glycoprotein. These features are the basis for most of the interactions occurring during azole therapy (e.g., in severely ill patients in the hospital who are treated with multiple drugs).
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PMID:Drug interactions during therapy with three major groups of antimicrobial agents. 1655 82

Quinacrine (QA), an antimalarial drug used for over seven decades, has been found to have potent antiprion activity in vitro. To determine whether QA can be used to treat prion diseases, we investigated its metabolism and ability to traverse the blood-brain barrier in mice. In vitro and in vivo, we identified by liquid chromatography-tandem mass spectrometry the major metabolic pathway of QA as N-desethylation and compared our results with an authentic reference compound. The major human cytochrome (P450) isoforms involved in QA mono-desethylation were identified as CYP3A4/5 by using specific chemical and antibody inhibition as well as cDNA-expressed P450 studies. QA transport from the basolateral to apical side in multidrug resistance protein 1 gene (MDR1)-transfected Madin-Darby canine kidney (MDCK) cells was markedly greater than in control MDCK cells and was inhibited by the potent P-glycoprotein (P-gp) inhibitor GG918 (N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-iso-1-quinolynyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine). In MDR1-knockout (KO) mice, QA brain levels were 6 to 9 times higher after a single i.v. dose of 2 mg/kg QA and 49 times higher after multiple oral doses of 10 mg/kg/day QA for 7 days, compared with those in wild-type (WT) FVB mice. In contrast, the QA levels in plasma, liver, spleen, and kidney were similar after a single 2 mg/kg i.v. dose and <2 times greater after 10 mg/kg oral doses in MDR1-KO mice compared with WT mice. These results indicate that P-gp plays a critical role in transporting QA from the brain.
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PMID:Quinacrine is mainly metabolized to mono-desethyl quinacrine by CYP3A4/5 and its brain accumulation is limited by P-glycoprotein. 1658 45

In this study, we investigated the applicability of C3A--a human hepatocyte cell line--as a predicting tool for drug metabolism by applying tissue-engineering methods. Cultivation of C3A cells within alginate scaffolds induced the formation of spheroids with enhanced drug metabolism activities compared to that of two-dimensional (2-D) monolayer cultures. The spheroid formation process was demonstrated via histology, immunohistochemistry, and transmission electron microscope (TEM) analyses. The C3A spheroids displayed multilayer cell morphology, characterized by a large number of tight junctions, polar cells, and bile canaliculi, similar to spheroids of primary hepatocytes. Spheroid formation was accompanied by a reduction in P-glycoprotein (Pgp) gene expression and C3A cell proliferation was limited mainly to cells on the spheroid outskirt. The 3-D constructs maintained a nearly constant cell number according to MTT assay. Drug metabolism by the two most important cytochrome p-450 (CYP) enzymes in human liver, CYP1A2 and CYP3A4, was tested using preferred drugs. With CYP1A2, 3-fold enhancement in activity per cell was seen for converting ethoxyresorufin to resorufin compared to C3A cell monolayers. The spheroids responded to the inducer beta-naphthoflavone and to the inhibitor furafylline of CYP1A2. Enhanced metabolizing activity of CYP3A4, measured by the amount 6beta-testosterone formed from testosterone, and that of the phase II enzyme glucuronosyltransferases (UGT) further indicated that the tissue-engineered C3A spheroids may provide an efficient experimental tool for predicting drug activities by these CYPs. Moreover, the maintenance of constant cell number, as well as the elevated hepatocellular functions and drug metabolism activities, suggest that the tissue-engineered C3A may be applicable in replacement therapies.
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PMID:Enhancing the drug metabolism activities of C3A--a human hepatocyte cell line--by tissue engineering within alginate scaffolds. 1677 48


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