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Critical Reviews in Oncology/hematology Jun 2017Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this... (Review)
Review
Pancreatic cancer is a highly deadly disease: almost all patients develop metastases and conventional treatments have little impact on survival. Therapeutically, this tumor is poorly responsive, largely due to drug resistance. Accumulating evidence suggest that this chemoresistance is intimately linked to specific metabolic aberrations of pancreatic cancer cells, notably an increased use of glucose and the amino acid glutamine fueling anabolic processes. Altered metabolism contributes also to modulation of apoptosis, angiogenesis and drug targets, conferring a resistant phenotype. As a modality to overcome chemoresistance, a variety of experimental compounds inhibiting key metabolic pathways emerged as a promising approach to potentiate the standard treatments for pancreatic cancer in preclinical studies. These results warrant confirmation in clinical trials. Thus, this review summarizes the impact of metabolic aberrations from the perspective of drug resistance and discusses possible novel applications of metabolic inhibition for the development of more effective drugs against pancreatic cancer.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Energy Metabolism; Humans; Pancreatic Neoplasms
PubMed: 28477742
DOI: 10.1016/j.critrevonc.2017.03.026 -
Nutrients Oct 2019Adipose tissue is a highly metabolically-active tissue that senses and secretes hormonal and lipid mediators that facilitate adaptations to metabolic tissues. In recent... (Review)
Review
Adipose tissue is a highly metabolically-active tissue that senses and secretes hormonal and lipid mediators that facilitate adaptations to metabolic tissues. In recent years, the role of lipokines, which are lipid species predominantly secreted from adipose tissue that act as hormonal regulators in many metabolic tissues, has been an important area of research for obesity and diabetes. Previous studies have identified that these secreted lipids, including palmitoleate, 12,13-diHOME, and fatty acid-hydroxy-fatty acids (FAHFA) species, are important regulators of metabolism. Moreover, environmental factors that directly affect the secretion of lipokines such as diet, exercise, and exposure to cold temperatures constitute attractive therapeutic strategies, but the mechanisms that regulate lipokine stimulation have not been thoroughly reviewed. In this study, we will discuss the chemical characteristics of lipokines that position them as attractive targets for chronic disease treatment and prevention and the emerging roles of lipokines as regulators of inter-tissue communication. We will define the target tissues of lipokines, and explore the ability of lipokines to prevent or delay the onset and development of chronic diseases. Comprehensive understanding of the lipokine synthesis and lipokine-driven regulation of metabolic outcomes is instrumental for developing novel preventative and therapeutic strategies that harness adipose tissue-derived lipokines.
Topics: Adipose Tissue; Cold Temperature; Diet; Exercise; Humans; Lipid Metabolism
PubMed: 31614481
DOI: 10.3390/nu11102422 -
Yakugaku Zasshi : Journal of the... 2015Drug-induced hepatotoxicity is of concern in drug discovery and development. Reactive metabolites generated by drug metabolizing enzymes in the liver contribute to the... (Review)
Review
Drug-induced hepatotoxicity is of concern in drug discovery and development. Reactive metabolites generated by drug metabolizing enzymes in the liver contribute to the induction of hepatotoxicity. Therefore, drug-induced hepatotoxicity, drug metabolism, and pharmacokinetics were evaluated in vitro and in vivo in this pre-clinical study. First, hepatotoxicity was tested in vitro using three-dimensional hepatocyte cultures. Hepatocyte spheroids formed in the three-dimensional culture systems maintain various liver functions such as the expression of drug metabolizing enzymes. High dose exposure to acetaminophen (APAP) induces hepatotoxicity because of the formation of reactive metabolites by CYP. Using fluorescence imaging, we observed that cell viability and glutathione levels were reduced in hepatocyte spheroids exposed to APAP mediated by the metabolic activation of CYP. On the other hand, there are species differences in the expression of drug metabolizing enzymes and metabolite profiles between animals and humans. Therefore, chimeric mice transfected with human hepatocytes were used for the in vivo assessment of metabolic profiles in humans. We found that drug metabolism and pharmacokinetics mediated by CYP and non-CYP enzymes, such as UDP-glucuronosyltransferase and aldehyde oxidase, in chimeric mice with humanized liver were similar to those in humans. The combination of in vitro and in vivo assessments using spheroids and chimeric mice with humanized liver, respectively, during the screening of drug candidates may help to reveal hepatotoxicity induced by the formation of metabolites.
Topics: Acetaminophen; Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury; Chimera; Humans; Liver; Mice; Pharmaceutical Preparations; Pharmacokinetics; Rats; Species Specificity
PubMed: 26521876
DOI: 10.1248/yakushi.15-00200 -
Current Neuropharmacology 2019Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a... (Review)
Review
BACKGROUND
Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a patient's drug metabolizing capacity merely from his or her genotype can lead to false prediction. Non-genetic host factors (age, sex, disease states) and environmental factors (nutrition, comedication) can transiently alter the enzyme expression and activities resulting in genotypephenotype mismatch. Although valproic acid is a well-tolerated anticonvulsant, pediatric patients are particularly vulnerable to valproate injury that can be partly attributed to the age-related differences in metabolic pathways.
METHODS
CYP2C9 mediated oxidation of valproate, which is the minor metabolic pathway in adults, appears to become the principal route in children. Genetic and non-genetic variations in CYP2C9 activity can result in significant inter- and intra-individual differences in valproate pharmacokinetics and valproate induced adverse reactions.
RESULTS
The loss-of-function alleles, CYP2C9*2 or CYP2C9*3, display significant reduction in valproate metabolism in children; furthermore, low CYP2C9 expression in patients with CYP2C9*1/*1 genotype also leads to a decrease in valproate metabolizing capacity. Due to phenoconversion, the homozygous wild genotype, expected to be translated to CYP2C9 enzyme with normal activity, is transiently switched into poor (or extensive) metabolizer phenotype.
CONCLUSION
Novel strategy for valproate therapy adjusted to CYP2C9-status (CYP2C9 genotype and CYP2C9 expression) is strongly recommended in childhood. The early knowledge of pediatric patients' CYP2C9-status facilitates the optimization of valproate dosing which contributes to the avoidance of misdosing induced adverse reactions, such as abnormal blood levels of ammonia and alkaline phosphatase, and improves the safety of children's anticonvulsant therapy.
Topics: Adult; Age Factors; Anticonvulsants; Biosynthetic Pathways; Child; Cytochrome P-450 CYP2C9; Epilepsy; Genotype; Humans; Phenotype; Polymorphism, Genetic; Valproic Acid
PubMed: 29119932
DOI: 10.2174/1570159X15666171109143654 -
Journal of Personalized Medicine Jul 2023Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further.... (Review)
Review
Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further. Treatments for mental disorders, such as depression, are available, but their effect is limited due to patients' (genetic) heterogeneity, low treatment compliance and frequent side effects. In general, only one-third of the patients respond to treatment. Today, medication selection in psychiatry relies on a trial-and-error approach based mainly on physicians' experience. Pharmacogenetic (PGx) testing can help in this process by determining the person-specific genetic factors that may predict clinical response and side effects associated with genetic variants that impact drug-metabolizing enzymes, drug transporters or drug targets. PGxis a discipline that investigates genetic factors that affect the absorption, metabolism, and transport of drugs, thereby affecting therapy outcome. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Studies in depressed patients show that genotyping of drug-metabolizing enzymes can increase the effectiveness of treatment, which could benefit millions of patients worldwide. This review highlights these studies, gives recommendations and provides future perspectives on how to proceed with PGx testing. Finally, it is recommended to consider genotyping for and , when there is an indication (side effects or inefficacy).
PubMed: 37511796
DOI: 10.3390/jpm13071183 -
Pharmaceutical Research Sep 2009Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux... (Review)
Review
Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme.
Topics: Administration, Oral; Animals; Biological Availability; Biotransformation; Carrier Proteins; Half-Life; Humans; Pharmacokinetics
PubMed: 19568696
DOI: 10.1007/s11095-009-9924-0 -
Biochimica Et Biophysica Acta Sep 2016The so-called xenobiotic receptors (XRs) have functionally evolved into cellular sensors for both endogenous and exogenous stimuli by regulating the transcription of... (Review)
Review
The so-called xenobiotic receptors (XRs) have functionally evolved into cellular sensors for both endogenous and exogenous stimuli by regulating the transcription of genes encoding drug-metabolizing enzymes and transporters, as well as those involving energy homeostasis, cell proliferation, and/or immune responses. Unlike prototypical steroid hormone receptors, XRs are activated through both direct ligand-binding and ligand-independent (indirect) mechanisms by a plethora of structurally unrelated chemicals. This review covers research literature that discusses direct vs. indirect activation of XRs. A particular focus is centered on the signaling control of the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), and the aryl hydrocarbon receptor (AhR). We expect that this review will shed light on both the common and distinct mechanisms associated with activation of these three XRs. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
Topics: Animals; Constitutive Androstane Receptor; Energy Metabolism; Gene Expression Regulation; Heat-Shock Proteins; Humans; Inactivation, Metabolic; Intercellular Signaling Peptides and Proteins; Liver; Mitogen-Activated Protein Kinases; Phosphorylation; Pregnane X Receptor; Receptors, Aryl Hydrocarbon; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Signal Transduction; Xenobiotics
PubMed: 26877237
DOI: 10.1016/j.bbagrm.2016.02.006 -
Scientific Reports Jan 2021Biohybrids composed of microorganisms and nanoparticles have emerged as potential systems for bioenergy and high-value compound production from CO and light energy, yet...
Biohybrids composed of microorganisms and nanoparticles have emerged as potential systems for bioenergy and high-value compound production from CO and light energy, yet the cellular and metabolic processes within the biological component of this system are still elusive. Here we dissect the biohybrid composed of the anaerobic acetogenic bacterium Moorella thermoacetica and cadmium sulphide nanoparticles (CdS) in terms of physiology, metabolism, enzymatics and transcriptomic profiling. Our analyses show that while the organism does not grow on L-cysteine, it is metabolized to acetate in the biohybrid system and this metabolism is independent of CdS or light. CdS cells have higher metabolic activity, despite an inhibitory effect of Cd on key enzymes, because of an intracellular storage compound linked to arginine metabolism. We identify different routes how cysteine and its oxidized form can be innately metabolized by the model acetogen and what intracellular mechanisms are triggered by cysteine, cadmium or blue light.
Topics: Acetates; Biological Transport; Cadmium; Carbon; Carbon Isotopes; Complex Mixtures; Cysteine; Energy Metabolism; Gene Expression Regulation, Bacterial; Light; Magnetic Resonance Spectroscopy; Moorella; Oxidation-Reduction; Transcriptome
PubMed: 33495538
DOI: 10.1038/s41598-021-81103-z -
Chemical Research in Toxicology Feb 2009Guidance from the Food and Drug Administration on drug interaction studies does not include a specific section on contributions of metabolites to observed inhibitory... (Review)
Review
Qualitative analysis of the role of metabolites in inhibitory drug-drug interactions: literature evaluation based on the metabolism and transport drug interaction database.
Guidance from the Food and Drug Administration on drug interaction studies does not include a specific section on contributions of metabolites to observed inhibitory drug-drug interactions, and the quantitative role of drug metabolites in inhibitory drug-drug interactions is not presently known. The current work was undertaken to evaluate what fraction of inhibitors of common drug-metabolizing enzymes [cytochrome P450 (P450) 1A2, 2E1, 2D6, 2C9, 2C19, 2C8, 2B6, and 3A4] have circulating metabolites that may contribute to observed in vivo interactions. A literature analysis was conducted using the Metabolism and Transport Drug Interaction Database to identify all precipitants (i.e., inhibitors) that cause more than a 20% increase in the area under the plasma concentration-time curve (AUC) of marker substrates. The database, PubMed, and product labels were then used to determine whether circulating metabolites were present after administration of these inhibitors. Of the total of 129 inhibitors identified, 106 were confirmed to have metabolites that circulate in plasma. An additional 14 inhibitors were identified that are extensively metabolized but whose metabolites either have not been identified or have not been investigated. Hence, only 7% of the inhibitors did not have circulating metabolites. Of the 21 potent inhibitors (>or=5-fold increase in AUC) currently known, 17 had circulating metabolites, and the remaining four were all extensively metabolized. On the basis of available in vitro data, 24 of all of the inhibitors were mechanism-based inactivators of P450 enzymes, while 105 were characterized as reversible inhibitors. In vitro evaluation of inhibition potential was conducted for only 32% of the circulating metabolites of the inhibitors. In conclusion, circulating metabolites are often present with inhibitors of P450 enzymes, suggesting a need for increased efforts to characterize the inhibitory potency of metabolites of candidate drugs and for newer models for in vitro to in vivo extrapolations.
Topics: Area Under Curve; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Databases, Factual; Drug Interactions; Enzyme Inhibitors; Pharmaceutical Preparations
PubMed: 19216580
DOI: 10.1021/tx800491e -
Physiology & Behavior Dec 2015Until recently, the general belief was that non-nutritive sweeteners (NNSs) were healthy sugar substitutes because they provide sweet taste without calories or glycemic... (Review)
Review
Until recently, the general belief was that non-nutritive sweeteners (NNSs) were healthy sugar substitutes because they provide sweet taste without calories or glycemic effects. However, data from several epidemiological studies have found that consumption of NNSs, mainly in diet sodas, is associated with increased risk to develop obesity, metabolic syndrome, and type 2 diabetes. The main purpose of this article is to review recent scientific evidence supporting potential mechanisms that explain how "metabolically inactive" NNSs, which have few, if any, calories, might promote metabolic dysregulation. Three potential mechanisms, which are not mutually exclusive, are presented: 1) NNSs interfere with learned responses that contribute to control glucose and energy homeostasis, 2) NNSs interfere with gut microbiota and induce glucose intolerance, and 3) NNSs interact with sweet-taste receptors expressed throughout the digestive system that play a role in glucose absorption and trigger insulin secretion. In addition, recent findings from our laboratory showing an association between individual taste sensitivity to detect sucralose and sucralose's acute effects on metabolic response to an oral glucose load are reported. Taken as a whole, data support the notion that NNSs have metabolic effects. More research is needed to elucidate the mechanisms by which NNSs may drive metabolic dysregulation and better understand potential effects of these commonly used food additives.
Topics: Animals; Energy Metabolism; Enteroendocrine Cells; Humans; Non-Nutritive Sweeteners
PubMed: 26095119
DOI: 10.1016/j.physbeh.2015.06.024