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)

Major neurologic complications secondary to cyclosporine are well documented and are known to include confusion, cortical blindness, seizure, spasticity, paresis, ataxia and coma. Most previous reports attribute these to white matter central nervous system (CNS) lesions or white/grey matter border lesions. Many predisposing factors have been identified, including: elevated levels of cyclosporine, hypomagnesemia, hypocholesterolemia, aluminium toxicity, high dose steroids, hypertension and infection. However CNS events attributed to cyclosporine have been reported without any of these risk factors. We report a case of a child developing multiple white and grey matter thalamic and cortical lesions along with acute neurologic deterioration, and then review cyclosporine mediated CNS injury, including the roles of P-glycoprotein and cyclophilin.
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PMID:Cyclosporine-induced white and grey matter central nervous system lesions in a pediatric renal transplant patient. 1008 60

Elucidating the molecular function of hu MDR 1 protein (also called P-glycoprotein or P-gp 1) and the precise role this protein plays in clinically relevant tumor drug resistance remains a perplexing problem. Hundreds of reports over the past decades summarize a dizzying array of observations relevant to hu MDR 1 protein function. A dominant model in the MDR literature that is used to explain many observations is the well known "drug pump" model first suggested by Keld Dano in 1973 [1]. Although this model has proved useful in conceptualizing additional experiments, it violates fundamental laws of biology and chemistry and in well over a decade of intense effort, active outward drug pumping via hu MDR 1 protein has still never been unequivocally measured. Also, in recent years it has become clear that the drug pump model cannot explain several important phenomena that are highly relevant to the cancer clinic. Thus, other models have also proved increasingly popular. One is the altered partitioning model, which does not violate fundamental laws, is consistent with the vast majority of available data, and has important predictive ability. This newer model has several novel facets that are relevant for cancer pharmacology, and that help explain phenomena not explained by the drug pump model. The basic principle of this model is that MDR proteins do not directly transport drugs, but that their altered expression leads to altered regulation of ion transport or signal transduction that is critical for setting key biophysical parameters of the cell (e.g. compartmental pH and membrane potentials) that dictate relative passive diffusion of drugs as well as important signal transduction linked to the cytotoxic actions of these drugs. Along with debate over the molecular details of hu MDR 1 function, additional controversy surrounds the precise role of hu MDR 1 in the clinic. Many investigators now debate the significance of its function (regardless of precise mechanism) with regard to "real" drug resistance phenotypes exhibited in the clinic. I believe that thorough debate on the pros and cons of various molecular models for hu MDR 1 function will help to address confusion over the clinical relevance of hu MDR1. In the current atmosphere of disappointment over the relative success of clinical trials based in large part on the logic of the drug pump model, it is important that we not lose sight of critical points. Namely, hu MDR 1 protein remains an extremely important window in on the complex pathways that lead to induced chemotherapeutic drug resistance. Exploring the rationale behind newer models for hu MDR 1 function leads to key predictions that can be tested.
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PMID:What is the precise role of human MDR 1 protein in chemotherapeutic drug resistance? 1063 78

Prediction of P-glycoprotein substrate specificity (S(PGP)) can be viewed as a constituent part of a compound's "pharmaceutical profiling" in drug design. This task is difficult to achieve due to several factors that raised many contradictory opinions: (i) the disparity between the S(PGP) values obtained in different assays, (ii) the confusion between Pgp substrates and inhibitors, (iii) the confusion between lipophilicity and amphiphilicity of Pgp substrates, and (iv) the dilemma of describing class-specific relationships when Pgp has no binding sites of high ligand specificity. In this work, we compiled S(PGP) data for 1000 compounds. All data were represented in a binary format, assigning S(PGP) = 1 for substrates and S(PGP) = 0 for non-substrates. Each value was ranked according to the reliability of experimental assay. Two data sets were considered. Set 1 included 220 compounds with S(PGP) from polarized transport across MDR1 transfected cell monolayers. Set 2 included the entire list of 1000 compounds, with S(PGP) values of generally lower reliability. Both sets were analysed using a stepwise classification structure-activity relationship (C-SAR) method, leading to derivation of simple rules for crude estimation of S(PGP) values. The obtained rules are based on the following factors: (i) compound's size expressed through molar weight or volume, (ii) H-accepting given by the Abraham's beta (that can be crudely approximated by the sum of O and N atoms), and (iii) ionization given by the acid and base pKa values. Very roughly, S(PGP) can be estimated by the "rule of fours". Compounds with (N + O) > or = 8, MW > 400 and acid pKa > 4 are likely to be Pgp substrates, whereas compounds with (N + O) < or = 4, MW < 400 and base pKa < 8 are likely to be non-substrates. The obtained results support the view that Pgp functioning can be compared to a complex "mini-pharmacokinetic" system with fuzzy specificity. This system can be described by a probabilistic version of Abraham's solvation equation, suggesting a certain similarity between Pgp transport and chromatographic retention. The chromatographic model does not work in the case of "marginal" compounds with properties close to the "global" physicochemical cut-offs. In the latter case various class-specific rules must be considered. These can be associated with the "amphiphilicity" and "biological similarity" of compounds. The definition of class-specific effects entails construction of the knowledge base that can be very useful in ADME profiling of new drugs.
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PMID:Classification analysis of P-glycoprotein substrate specificity. 1520 28

CYP3A is one of the most important drug-metabolizing enzymes, determining the first-pass metabolism, oral bioavailability, and elimination of many drugs. It is also an important determinant of variable drug exposure and is involved in many drug-drug interactions. Recent studies with CYP3A knockout and transgenic mice have yielded a number of key insights that are important to consider during drug discovery and development. For instance, studies with tissue-specific CYP3A-transgenic mice have highlighted the importance of intestinal CYP3A-dependent metabolism. They also revealed that intestinal CYP3A plays an important role in the regulation of various drug-handling systems in the liver. Intestinal CYP3A activity can thus have far-reaching pharmacological effects. Besides CYP3A, the active drug efflux transporter P-glycoprotein also has a strong effect on the pharmacokinetics of numerous drugs. CYP3A and P-glycoprotein have an extensive overlap in their substrate spectrum. It has been hypothesized that for many drugs, the combined activity of CYP3A and P-glycoprotein makes for efficient intestinal first-pass metabolism of orally administered drugs as a result of a potentially synergistic collaboration. However, there is only limited in vitro and in vivo evidence for this hypothesis. There has also been some confusion in the field about what synergy actually means in this case. Our recent studies with Cyp3a/P-glycoprotein combination knockout mice have provided further insights into the CYP3A-P-glycoprotein interplay. We here present our view of the status of the synergy hypothesis and an attempt to clarify the existing confusion about synergy. We hope that this will facilitate further critical testing of the hypothesis and improve communication among researchers. Above all, the recent findings and insights into the interplay between CYP3A and P-glycoprotein may have implications for improving oral drug bioavailability and reducing adverse side effects.
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PMID:A critical analysis of the interplay between cytochrome P450 3A and P-glycoprotein: recent insights from knockout and transgenic mice. 2149 Jan 28