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Neuroscience and Biobehavioral Reviews Sep 2014Most drugs are metabolized in the liver by cytochromes P450 (CYPs). Stress can modify CYP-catalyzed drug metabolism and subsequently, the pharmacokinetic profile of a... (Review)
Review
Most drugs are metabolized in the liver by cytochromes P450 (CYPs). Stress can modify CYP-catalyzed drug metabolism and subsequently, the pharmacokinetic profile of a drug. Current evidence demonstrates a gene-, stress- and species-specific interference in stress-mediated regulation of genes encoding the major drug-metabolizing CYP isozymes. Stress-induced up-regulation of CYPs that metabolize the majority of prescribed drugs can result in their increased metabolism and consequently, in failure of pharmacotherapy. In contrast, stress-induced down-regulation of CYP isozymes, including CYP2E1 and CYP2B1/2, potentially reduces metabolism of several toxicants and specific drugs-substrates resulting in increased levels and altered toxicity. The primary stress effectors, the adrenergic receptor-linked pathways and glucocorticoids, play primary and distinct roles in stress-mediated regulation of CYPs. Evidence demonstrates that stress regulates major drug metabolizing CYP isozymes, suggesting that stress should be considered to ensure pharmacotherapy efficacy and minimize drug toxicity. A detailed understanding of the molecular events underlying the stress-dependent regulation of drug metabolizing CYPs is crucial both for the design of new drugs and for physiology-based pharmacokinetic and pharmacodynamic modeling.
Topics: Animals; Cytochrome P-450 Enzyme System; Humans; Pharmacokinetics; Stress, Psychological
PubMed: 24877684
DOI: 10.1016/j.neubiorev.2014.05.011 -
Fundamental & Clinical Pharmacology 1990The molecular mechanisms of 3 genetic polymorphisms of drug metabolism have been studied at the level of enzyme activity, enzyme protein and RNA/DNA. As regards... (Review)
Review
The molecular mechanisms of 3 genetic polymorphisms of drug metabolism have been studied at the level of enzyme activity, enzyme protein and RNA/DNA. As regards debrisoquine/sparteine polymorphism, cytochrome P-450IID6 was absent in livers of poor metabolizers; aberrant splicing of premRNA of P-450IID6 may be responsible for this. Moreover, 3 mutant alleles of the P-450IID6 locus on chromosome 22 associated with the poor metabolizer phenotype were identified by Southern analysis of leucocyte DNA. The presence of 2 identified mutant alleles allowed the prediction of the phenotype in approximately 25% of poor metabolizers. The additional gene-inactivating mutations which are operative in the remainder of poor metabolizers are now being studied. Regarding mephenytoin polymorphism, although the deficient reaction, S-mephenytoin 4'-hydroxylation, has been well defined in human liver microsomes, the mechanism of this polymorphism remains unclear. All antibodies prepared to date against cytochrome P-450 fractions with this activity recognize several structurally similar enzymes and several cDNAs related to these enzymes have been isolated and expressed in heterologous systems. However, which isozyme is affected by this polymorphism is not known. As regards N-acetylation polymorphism, N-acetyltransferases have been purified from human liver, specific antibodies prepared; it was observed that immunoreactive N-acetyltransferase is decreased or undetectable in liver of "slow acetylators". Two genes that encode functional N-acetyltransferase were characterized. The product of one of these genes has identical activity and characteristics as the polymorphic liver enzyme. Cloned DNA from rapid and slow acetylator individuals has been analyzed to identify the structural or regulatory defect that causes deficient N-acetyltransferase.
Topics: Acetylation; Arylamine N-Acetyltransferase; Cytochrome P-450 Enzyme System; Humans; Hydroxylation; Liver; Oxidation-Reduction; Pharmaceutical Preparations; Phenotype; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length
PubMed: 1982880
DOI: 10.1111/j.1472-8206.1990.tb00041.x -
Trends in Molecular Medicine Sep 2009Protein S-nitrosylation constitutes a large part of the ubiquitous influence of nitric oxide on cellular signal transduction and accumulating evidence indicates... (Review)
Review
Protein S-nitrosylation constitutes a large part of the ubiquitous influence of nitric oxide on cellular signal transduction and accumulating evidence indicates important roles for S-nitrosylation both in normal physiology and in a broad spectrum of human diseases. Here we review recent findings that implicate S-nitrosylation in cardiovascular, pulmonary, musculoskeletal and neurological (dys)function, as well as in cancer. The emerging picture shows that, in many cases, pathophysiology correlates with hypo- or hyper-S-nitrosylation of specific protein targets rather than a general cellular insult due to loss of or enhanced nitric oxide synthase activity. In addition, it is increasingly evident that dysregulated S-nitrosylation can not only result from alterations in the expression, compartmentalization and/or activity of nitric oxide synthases, but can also reflect a contribution from denitrosylases, including prominently the S-nitrosoglutathione (GSNO)-metabolizing enzyme GSNO reductase. Finally, because exogenous mediators of protein S-nitrosylation or denitrosylation can substantially affect the development or progression of disease, potential therapeutic agents that modulate S-nitrosylation could well have broad clinical utility.
Topics: Animals; Disease; Health; Humans; Nitrates; Nitric Oxide; Nitrosation; Proteins; Signal Transduction
PubMed: 19726230
DOI: 10.1016/j.molmed.2009.06.007 -
Methods in Molecular Biology (Clifton,... 2022Cell polarity is a common feature of many living cells, especially epithelial cells, and plays important roles in development, tissue homeostasis, and diseases....
Cell polarity is a common feature of many living cells, especially epithelial cells, and plays important roles in development, tissue homeostasis, and diseases. Therefore, the signaling pathways involved in establishing and maintaining cell polarity are tightly controlled. Protein S-palmitoylation has been recently recognized as an important posttranslational modification involved in cell polarity, via dynamic covalent attachment of fatty acyl groups to the cysteine residues of cell polarity proteins. Here, we describe the methods to study the function and regulation of S-palmitoylation of cell polarity proteins.
Topics: Cell Polarity; Cysteine; Lipoylation; Protein Processing, Post-Translational; Proteins
PubMed: 35147938
DOI: 10.1007/978-1-0716-2035-9_7 -
International Journal of Molecular... Oct 2020S-glutathionylation, the post-translational modification forming mixed disulfides between protein reactive thiols and glutathione, regulates redox-based signaling events... (Review)
Review
S-glutathionylation, the post-translational modification forming mixed disulfides between protein reactive thiols and glutathione, regulates redox-based signaling events in the cell and serves as a protective mechanism against oxidative damage. S-glutathionylation alters protein function, interactions, and localization across physiological processes, and its aberrant function is implicated in various human diseases. In this review, we discuss the current understanding of the molecular mechanisms of S-glutathionylation and describe the changing levels of expression of S-glutathionylation in the context of aging, cancer, cardiovascular, and liver diseases.
Topics: Animals; Glutathione; Humans; Oxidation-Reduction; Oxidative Stress; Protein Processing, Post-Translational; Proteins; Signal Transduction
PubMed: 33143095
DOI: 10.3390/ijms21218113 -
Scientific Reports Dec 2021Cruciferous vegetables are rich sources of glucosinolates (GSLs). GSLs are degraded into isothiocyanates, which are potent anticarcinogens, by human gut bacteria....
Cruciferous vegetables are rich sources of glucosinolates (GSLs). GSLs are degraded into isothiocyanates, which are potent anticarcinogens, by human gut bacteria. However, the mechanisms and enzymes involved in gut bacteria-mediated GSL metabolism are currently unclear. This study aimed to elucidate the enzymes involved in GSL metabolism in lactic acid bacteria, a type of gut bacteria. Companilactobacillus farciminis KB1089 was selected as a lactic acid bacteria strain model that metabolizes sinigrin, which is a GSL, into allylisothiocyanate. The sinigrin-metabolizing activity of this strain is induced under glucose-absent and sinigrin-present conditions. A quantitative comparative proteomic analysis was conducted and a total of 20 proteins that were specifically expressed in the induced cells were identified. Three candidate proteins, β-glucoside-specific IIB, IIC, IIA phosphotransferase system (PTS) components (CfPttS), 6-phospho-β-glucosidase (CfPbgS) and a hypothetical protein (CfNukS), were suspected to be involved in sinigrin-metabolism and were thus investigated further. We hypothesize a pathway for sinigrin degradation, wherein sinigrin is taken up and phosphorylated by CfPttS, and subsequently, the phosphorylated entity is degraded by CfPbgS. As expression of both pttS and pbgS genes clearly gave Escherichia coli host strain sinigrin converting activity, these genes were suggested to be responsible for sinigrin degradation. Furthermore, heterologous expression analysis using Lactococcus lactis suggested that CfPttS was important for sinigrin degradation and CfPbgS degraded phosphorylated sinigrin.
Topics: Carbohydrate Metabolism; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Glucosinolates; Lactobacillus; Multigene Family; Proteome; Proteomics; Secondary Metabolism
PubMed: 34887468
DOI: 10.1038/s41598-021-03064-7 -
Cell Biochemistry and Biophysics Apr 2014Besides pharmacogenomics and drug dynamics, pharmacological properties of a drug could also arise from protein conformational switches. These switches would arise from... (Review)
Review
Besides pharmacogenomics and drug dynamics, pharmacological properties of a drug could also arise from protein conformational switches. These switches would arise from the following mechanisms: (a) slight shifts away from a protein's native conformation induced by mutation, (b) changes in the protein's environment allowing for structural rearrangements to form hitherto unknown conformations, (c) parsing the protein into foldable polypeptide fragment(s) by either proteolysis of the native structure or (d) perturbation of the native conformation to generate polypeptide fragment(s). These switches are modulated by changes in the protein's matrix properties such as pH, temperature, ligands-their nature, concentration and complexes; micronutrients, oxidant/antioxidant status and metabolic products within the functional environment of the protein. The pharmacological implications of these are discussed in light of polypharmacology arising from protein isomerism, cross-pharmacology, possible decreases in both the expressible and expressed protein population and metabolic reprogramming-and ultimately, how these factors relate to diseases. Further implications include variational drug toxicity and drug response idiosyncrasies. Another important consequence is that the "whole life" history of the individual would play an active role in that individual's response to disease severity and drug response up to that very moment and is prone to variations with changes in pre-disposing factors.
Topics: Evolution, Molecular; Humans; Metabolism; Pharmacology; Protein Conformation; Proteins; Proteostasis Deficiencies
PubMed: 24068517
DOI: 10.1007/s12013-013-9748-8 -
Pharmaceutical Research Jan 1992Nasal delivery is a potential alternative for systemic availability of drugs restricted to intravenous administration, such as peptide and protein drugs. Although nasal... (Review)
Review
Nasal delivery is a potential alternative for systemic availability of drugs restricted to intravenous administration, such as peptide and protein drugs. Although nasal delivery avoids the hepatic first-pass effect, the enzymatic barrier of the nasal mucosa creates a pseudo-first-pass effect. The xenobiotic metabolic activity in the nasal epithelium has been investigated in several species including humans. The Phase I, cytochrome P-450 enzymes have been studied extensively for their toxicological significance, since these enzymes metabolize inhaled pollutants into reactive metabolites which may induce nasal tumors. The cytochrome P-450 activity in the olfactory region of the nasal epithelium is higher even than in the liver, mainly because of a three- to fourfold higher NADPH-cytochrome P-450 reductase content. Phase II activity has also been found in the nasal epithelium. The delivery of peptides and proteins has been hindered by the peptidase and protease activity in the nasal mucosa. The predominant enzyme appears to be aminopeptidase among other exopeptidases and endopeptidases. The absorption of peptide drugs can be improved by using aminoboronic acid derivatives, amastatin, and other enzyme inhibitors as absorption enhancers. It is possible that some of the surfactants, e.g., bile salts, increase absorption by inhibiting the proteolytic enzymes. Thus, in addition to the permeation barriers, there also exists an enzymatic barrier to nasal drug delivery, which is created by metabolic enzymes in the nasal epithelium.
Topics: Absorption; Administration, Intranasal; Humans; Nasal Mucosa; Oxidation-Reduction; Peptides; Pharmaceutical Preparations; Protease Inhibitors; Proteins
PubMed: 1589391
DOI: 10.1023/a:1018911206646 -
EMBO Reports Jul 2021In eukaryotic cells, DNA is tightly packed with the help of histone proteins into chromatin. Chromatin architecture can be modified by various post-translational... (Review)
Review
In eukaryotic cells, DNA is tightly packed with the help of histone proteins into chromatin. Chromatin architecture can be modified by various post-translational modifications of histone proteins. For almost 60 years now, studies on histone lysine acetylation have unraveled the contribution of this acylation to an open chromatin state with increased DNA accessibility, permissive for gene expression. Additional complexity emerged from the discovery of other types of histone lysine acylations. The acyl group donors are products of cellular metabolism, and distinct histone acylations can link the metabolic state of a cell with chromatin architecture and contribute to cellular adaptation through changes in gene expression. Currently, various technical challenges limit our full understanding of the actual impact of most histone acylations on chromatin dynamics and of their biological relevance. In this review, we summarize the state of the art and provide an overview of approaches to overcome these challenges. We further discuss the concept of subnuclear metabolic niches that could regulate local CoA availability and thus couple cellular metabolisms with the epigenome.
Topics: Acetylation; Acylation; Chromatin; Histones; Protein Processing, Post-Translational
PubMed: 34159701
DOI: 10.15252/embr.202152774 -
FEMS Yeast Research Sep 2015Glucose is the primary source of energy for the budding yeast Saccharomyces cerevisiae. Although yeast cells can utilize a wide range of carbon sources, presence of... (Review)
Review
Glucose is the primary source of energy for the budding yeast Saccharomyces cerevisiae. Although yeast cells can utilize a wide range of carbon sources, presence of glucose suppresses molecular activities involved in the use of alternate carbon sources as well as it represses respiration and gluconeogenesis. This dominant effect of glucose on yeast carbon metabolism is coordinated by several signaling and metabolic interactions that mainly regulate transcriptional activity but are also effective at post-transcriptional and post-translational levels. This review describes effects of glucose repression on yeast carbon metabolism with a focus on roles of the Snf3/Rgt2 glucose-sensing pathway and Snf1 signal transduction in establishment and relief of glucose repression.
Topics: Carbon; Catabolite Repression; Energy Metabolism; Gene Expression Regulation, Fungal; Glucose; Monosaccharide Transport Proteins; Protein Serine-Threonine Kinases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 26205245
DOI: 10.1093/femsyr/fov068