-
Drug Metabolism and Disposition: the... Aug 2021This study aimed to comprehensively investigate the in vitro metabolism of statins. The metabolism of clinically relevant concentrations of atorvastatin, fluvastatin,...
This study aimed to comprehensively investigate the in vitro metabolism of statins. The metabolism of clinically relevant concentrations of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and their metabolites were investigated using human liver microsomes (HLMs), human intestine microsomes (HIMs), liver cytosol, and recombinant cytochrome P450 enzymes. We also determined the inhibitory effects of statin acids on their pharmacological target, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. In HLMs, statin lactones were metabolized to a much higher extent than their acid forms. Atorvastatin lactone and simvastatin (lactone) showed extensive metabolism [intrinsic clearance (CL) values of 3700 and 7400 µl/min per milligram], whereas the metabolism of the lactones of 2-hydroxyatorvastatin, 4-hydroxyatorvastatin, and pitavastatin was slower (CL 20-840 µl/min per milligram). The acids had CL values in the range <0.1-80 µl/min per milligram. In HIMs, only atorvastatin lactone and simvastatin (lactone) exhibited notable metabolism, with CL values corresponding to 20% of those observed in HLMs. CYP3A4/5 and CYP2C9 were the main statin-metabolizing enzymes. The majority of the acids inhibited HMG-CoA reductase, with 50% inhibitory concentrations of 4-20 nM. The present comparison of the metabolism and pharmacodynamics of the various statins using identical methods provides a strong basis for further application, e.g., comparative systems pharmacology modeling. SIGNIFICANCE STATEMENT: The present comparison of the in vitro metabolic and pharmacodynamic properties of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin and their metabolites using unified methodology provides a strong basis for further application. Together with in vitro drug transporter and clinical data, the present findings are applicable for use in comparative systems pharmacology modeling to predict the pharmacokinetics and pharmacological effects of statins at different dosages.
Topics: Biotransformation; Cytochrome P-450 Enzyme System; Cytosol; Drug Design; Drug Development; Hepatobiliary Elimination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inhibitory Concentration 50; Intestines; Liver; Metabolic Clearance Rate; Microsomes; Network Pharmacology
PubMed: 34045219
DOI: 10.1124/dmd.121.000406 -
Microbiology (Reading, England) Jun 2015Carnitine is a quaternary amine compound found at high concentration in animal tissues, particularly muscle, and is most well studied for its contribution to fatty acid... (Review)
Review
Carnitine is a quaternary amine compound found at high concentration in animal tissues, particularly muscle, and is most well studied for its contribution to fatty acid transport into mitochondria. In bacteria, carnitine is an important osmoprotectant, and can also enhance thermotolerance, cryotolerance and barotolerance. Carnitine can be transported into the cell or acquired from metabolic precursors, where it can serve directly as a compatible solute for stress protection or be metabolized through one of a few distinct pathways as a nutrient source. In this review, we summarize what is known about carnitine physiology and metabolism in bacteria. In particular, recent advances in the aerobic and anaerobic metabolic pathways as well as the use of carnitine as an electron acceptor have addressed some long-standing questions in the field.
Topics: Aerobiosis; Anaerobiosis; Animals; Bacterial Physiological Phenomena; Carnitine; Cold Temperature; Electron Transport; Hot Temperature; Hydrostatic Pressure; Metabolic Networks and Pathways; Osmotic Pressure; Stress, Physiological
PubMed: 25787873
DOI: 10.1099/mic.0.000080 -
International Journal of Molecular... Mar 2023Lymphoma is a heterogeneous group of diseases that often require their metabolism program to fulfill the demand of cell proliferation. Features of metabolism in lymphoma... (Review)
Review
Lymphoma is a heterogeneous group of diseases that often require their metabolism program to fulfill the demand of cell proliferation. Features of metabolism in lymphoma cells include high glucose uptake, deregulated expression of enzymes related to glycolysis, dual capacity for glycolytic and oxidative metabolism, elevated glutamine metabolism, and fatty acid synthesis. These aberrant metabolic changes lead to tumorigenesis, disease progression, and resistance to lymphoma chemotherapy. This metabolic reprogramming, including glucose, nucleic acid, fatty acid, and amino acid metabolism, is a dynamic process caused not only by genetic and epigenetic changes, but also by changes in the microenvironment affected by viral infections. Notably, some critical metabolic enzymes and metabolites may play vital roles in lymphomagenesis and progression. Recent studies have uncovered that metabolic pathways might have clinical impacts on the diagnosis, characterization, and treatment of lymphoma subtypes. However, determining the clinical relevance of biomarkers and therapeutic targets related to lymphoma metabolism is still challenging. In this review, we systematically summarize current studies on metabolism reprogramming in lymphoma, and we mainly focus on disorders of glucose, amino acids, and lipid metabolisms, as well as dysregulation of molecules in metabolic pathways, oncometabolites, and potential metabolic biomarkers. We then discuss strategies directly or indirectly for those potential therapeutic targets. Finally, we prospect the future directions of lymphoma treatment on metabolic reprogramming.
Topics: Humans; Glycolysis; Lymphoma; Metabolic Networks and Pathways; Glucose; Fatty Acids; Tumor Microenvironment
PubMed: 36982568
DOI: 10.3390/ijms24065493 -
Essays in Biochemistry Mar 2023Astrocytes show unique anatomical, morphological, and metabolic features to take up substrates from the blood and metabolize them for local delivery to active synapses... (Review)
Review
Astrocytes show unique anatomical, morphological, and metabolic features to take up substrates from the blood and metabolize them for local delivery to active synapses to sustain neuron function. In the present review, we specifically focus on key molecular aspects of energy and redox metabolism that facilitate this astrocyte-neuronal coupling in a controlled manner. Basal glycolysis is co-ordinated by the anaphase-promoting complex/cyclosome (APC/C)-Cdh1, a ubiquitin ligase that targets the proglycolytic enzyme 6-phosphofructokinase-2,6-bisphosphastate-3 (PFKFB3) for degradation. APC/C-Cdh1 activity is more robust in neurons than in astrocytes, which determine that PFKFB3 abundance and glycolytic rate are weaker in neurons. The low PFKFB3 activity in neurons facilitates glucose-6-phosphate oxidation via the pentose-phosphate pathway, which promotes antioxidant protection. Conversely, the high PFKFB3 activity in astrocytes allows the production and release of glycolytic lactate, which is taken up by neurons that use it as an oxidizable substrate. Importantly, the mitochondrial respiratory chain is tighter assembled in neurons than in astrocytes, thus the bioenergetic efficiency of mitochondria is higher in neurons. Because of this, the production of reactive oxygen species (mROS) by mitochondrial complex I is very low in neurons and very high in astrocytes. Such a naturally occurring high abundance of mROS in astrocytes physiologically determines a specific transcriptional fingerprint that contributes to sustaining cognitive performance. We conclude that the energy and redox metabolism of astrocytes must complementarily match that of neurons to regulate brain function and animal welfare.
Topics: Animals; Astrocytes; Energy Metabolism; Glycolysis; Oxidation-Reduction; Neurons
PubMed: 36805653
DOI: 10.1042/EBC20220075 -
Drug Metabolism Reviews Aug 2018Gut microbiota, one of the determinants of pharmacokinetics, has long been underestimated. It is now generally accepted that the gut microbiota plays an important role... (Review)
Review
Gut microbiota, one of the determinants of pharmacokinetics, has long been underestimated. It is now generally accepted that the gut microbiota plays an important role in drug metabolism during enterohepatic circulation either before drug absorption or through various microbial enzymatic reactions in the gut. In addition, some drugs are metabolized by the intestinal microbiota to specific metabolites that cannot be formed in the liver. More importantly, metabolizing drugs through the gut microbiota prior to absorption can alter the systemic bioavailability of certain drugs. Therefore, understanding intestinal flora-mediated drug metabolism is critical to interpreting changes in drug pharmacokinetics. Here, we summarize the effects of gut microbiota on drug pharmacokinetics, and propose that the influence of intestinal flora on pharmacokinetics should be organically related to the therapeutic effects and side effects of drugs. More importantly, we could rationally perform the strategy of intestinal microflora-mediated metabolism to design drugs.
Topics: Animals; Gastrointestinal Microbiome; Humans; Pharmacokinetics
PubMed: 30227749
DOI: 10.1080/03602532.2018.1497647 -
Molecular Metabolism Aug 2020ATP-dependent chromatin remodelers are evolutionarily conserved complexes that alter nucleosome positioning to influence many DNA-templated processes, such as... (Review)
Review
BACKGROUND
ATP-dependent chromatin remodelers are evolutionarily conserved complexes that alter nucleosome positioning to influence many DNA-templated processes, such as replication, repair, and transcription. In particular, chromatin remodeling can dynamically regulate gene expression by altering accessibility of chromatin to transcription factors.
SCOPE OF REVIEW
This review provides an overview of the importance of chromatin remodelers in the regulation of metabolic gene expression. Particular emphasis is placed on the INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers in both yeast and mammals. This review details discoveries from the initial identification of chromatin remodelers in Saccharomyces cerevisiae to recent discoveries in the metabolic requirements of developing embryonic tissues in mammals.
MAJOR CONCLUSIONS
INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers regulate the expression of energy metabolism pathways in S. cerevisiae and mammals in response to diverse nutrient environments. In particular, the INO80 complex organizes the temporal expression of gene expression in the metabolically synchronized S. cerevisiae system. INO80-mediated chromatin remodeling is also needed to constrain cell division during metabolically favorable conditions. Conversely, the BAF/PBAF remodeler regulates tissue-specific glycolytic metabolism and is disrupted in cancers that are dependent on glycolysis for proliferation. The role of chromatin remodeling in metabolic gene expression is downstream of the metabolic signaling pathways, such as the TOR pathway, a critical regulator of metabolic homeostasis. Furthermore, the INO80 and BAF/PBAF chromatin remodelers have both been shown to regulate heart development, the tissues of which have unique requirements for energy metabolism during development. Collectively, these results demonstrate that chromatin remodelers communicate metabolic status to chromatin and are a central component of homeostasis pathways that optimize cell fitness, organismal development, and prevent disease.
Topics: Animals; Chromatin; Chromatin Assembly and Disassembly; DNA-Binding Proteins; Gene Expression; Gene Expression Regulation; Metabolic Networks and Pathways; Metabolism; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Transcription Factors; Transcriptional Activation
PubMed: 32251664
DOI: 10.1016/j.molmet.2020.100973 -
Current Drug Metabolism 2021Infections and inflammation lead to a downregulation of drug metabolism and kinetics in experimental animals. These changes in the expression and activities of... (Review)
Review
BACKGROUND
Infections and inflammation lead to a downregulation of drug metabolism and kinetics in experimental animals. These changes in the expression and activities of drug-metabolizing enzymes may affect the effectiveness and safety of pharmacotherapy of infections and inflammatory conditions.
OBJECTIVE
In this review, we addressed the available evidence on the effects of malaria on drug metabolism activity and kinetics in rodents and humans.
RESULTS
An extensive literature review indicated that infection by Plasmodium spp consistently decreased the activity of hepatic Cytochrome P450s and phase-2 enzymes as well as the clearance of a variety of drugs in mice (lethal and non-lethal) and rat models of malaria. Malaria-induced CYP2A5 activity in the mouse liver was an exception. Except for paracetamol, pharmacokinetic trials in patients during acute malaria and in convalescence corroborated rodent findings. Trials showed that, in acute malaria, clearance of quinine, primaquine, caffeine, metoprolol, omeprazole, and antipyrine is slower and that AUCs are greater than in convalescent individuals.
CONCLUSION
Notwithstanding the differences between rodent models and human malaria, studies in P. falciparum and P. vivax patients confirmed rodent data showing that CYP-mediated clearance of antimalarials and other drugs is depressed during the symptomatic disease when rises in levels of acute-phase proteins and inflammatory cytokines occur. Evidence suggests that inflammatory cytokines and the interplay between malaria-activated NF-kB-signaling and cell pathways controlling phase 1/2 enzyme genes transcription mediate drug metabolism changes. The malaria-induced decrease in drug clearance may exacerbate drug-drug interactions, and the occurrence of adverse drug events, particularly when patients are treated with narrow-margin-of-safety medicines.
Topics: Animals; Antimalarials; Cytochrome P-450 Enzyme System; Drug Elimination Routes; Humans; Inactivation, Metabolic; Malaria; Metabolic Clearance Rate; Rodentia
PubMed: 33397251
DOI: 10.2174/1389200221999210101232057 -
Nucleic Acids Research Jan 2021Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major...
Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/.
Topics: Bacteria; DNA Methylation; Databases, Factual; Drugs, Investigational; Enzymes; Fungi; Histones; Humans; Inactivation, Metabolic; Internet; Metabolic Clearance Rate; Microbiota; Prescription Drugs; Protein Processing, Post-Translational; RNA, Long Noncoding; Software; Xenobiotics
PubMed: 33045737
DOI: 10.1093/nar/gkaa755 -
American Journal of Physiology.... Aug 2023A person's metabolic rate corresponds to the whole body level sum of all oxidative reactions occurring on the cellular level. The energy expenditure (EE) can be...
A person's metabolic rate corresponds to the whole body level sum of all oxidative reactions occurring on the cellular level. The energy expenditure (EE) can be categorized into various obligatory and facultative processes. In sedentary adults, basal metabolic rate is the largest contributor to total daily EE, and interindividual variability can be significant. Additional EE is required for digesting and metabolizing food, thermoregulatory adaptation to cold, and to support exercise and nonexercise body movements. Interindividual variability also exists for these EE processes, even after controlling for known factors. The complex mechanisms of interindividual variability in EE can have genetic and environmental origins and require further investigation. Exploration of interindividual variability in EE and its underlying factors holds importance to metabolic health, as it may predict disease risk, and be useful in the personalization of preventative and treatment strategies.
Topics: Adult; Humans; Energy Metabolism; Basal Metabolism; Exercise; Body Temperature Regulation; Adaptation, Physiological
PubMed: 37315156
DOI: 10.1152/ajpendo.00060.2023 -
Xenobiotica; the Fate of Foreign... May 2020Metabolism and transport of many drugs oscillate with times of the day (solar time), resulting in circadian time-dependent drug exposure and...
Metabolism and transport of many drugs oscillate with times of the day (solar time), resulting in circadian time-dependent drug exposure and pharmacokinetics.Time-dependent pharmacokinetics (also known as chronopharmacokinetics) is associated with time-varying drug effects and toxicity.This review summarizes drug-metabolizing enzymes and transporters with rhythmic expressions in the liver, intestine and/or kidney. Correlations of these diurnal proteins with circadian variations in drug exposure and effects/toxicity are covered. We also discuss the molecular mechanisms for circadian control of enzymes and transporters.Mechanism-based chronopharmacokinetics would facilitate a better understanding of chronopharmacology and the design of time-specific drug delivery systems, ultimately leading to improved drug efficacy and minimized toxicity.
Topics: Circadian Clocks; Circadian Rhythm; Drug Delivery Systems; Humans; Inactivation, Metabolic; Kidney; Liver; Membrane Transport Proteins; Metabolic Clearance Rate; Pharmaceutical Preparations
PubMed: 31544568
DOI: 10.1080/00498254.2019.1672120