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Xenobiotica; the Fate of Foreign... Jan 2020The review focuses on genetic variants of human flavin-containing monooxygenase 3 (FMO3) and their impact on enzyme activity, drug metabolism and disease.The majority of... (Review)
Review
The review focuses on genetic variants of human flavin-containing monooxygenase 3 (FMO3) and their impact on enzyme activity, drug metabolism and disease.The majority of FMO-mediated metabolism in adult human liver is catalyzed by FMO3. Some drugs are metabolized in human liver predominantly by FMO3, but most drug substrates of FMO3 are metabolized also by other enzymes, particularly cytochromes P-450, and the FMO3-catalyzed reaction is not the major route of metabolism.Rare variants that severely affect production or activity of FMO3 cause the disorder trimethylaminuria and impair metabolism of drug substrates of FMO3. More common variants, particularly p.[(Glu158Lys);(Glu308Gly)], can moderately affect activity of FMO3 and reduce metabolism of drug substrates , in some cases increasing drug efficacy or toxicity.Common variants of have been associated with a number of disorders, but additional studies are needed to confirm or refute such associations.Elevated plasma concentrations of trimethylamine -oxide, a product of an FMO3-catalyzed reaction, have been implicated in certain diseases, particularly cardiovascular disease. However, the evidence is often contradictory and additional work is required to establish whether trimethylamine -oxide is a cause, effect or biomarker of the disease.Genetic variants of other s are also briefly discussed.
Topics: Adult; Humans; Inactivation, Metabolic; Metabolism, Inborn Errors; Methylamines; Oxygenases; Polymorphism, Genetic
PubMed: 31317802
DOI: 10.1080/00498254.2019.1643515 -
Frontiers in Pharmacology 2023Many drugs have been shown to be metabolized by the human gut microbiome, but probiotic-driven drug-metabolizing capacity is rarely explored. Here, we developed an...
Many drugs have been shown to be metabolized by the human gut microbiome, but probiotic-driven drug-metabolizing capacity is rarely explored. Here, we developed an integrated metabolomics, culturomics, and bionics framework for systematically studying probiotics-driven drug metabolism. We discovered that 75% (27/36 of the assayed drugs) were metabolized by five selected probiotics, and drugs containing nitro or azo groups were more readily metabolized. As proof-of-principle experiments, we showed that Zhang (LCZ) could metabolize racecadotril to its active products, S-acetylthiorphan and thiorphan, in monoculture, in a near-real simulated human digestion system, and in an fecal co-culture system. However, a personalized effect was observed in the racecadotril-metabolizing activity of Zhang, depending on the individual's host gut microbiome composition. Based on data generated by our workflow, we proposed a possible mechanism of interactions among Zhang, racecadotril, and host gut microbiome, providing practical guidance for probiotic-drug co-treatment and novel insights into precision probiotics.
PubMed: 36778014
DOI: 10.3389/fphar.2023.1047863 -
International Journal of Molecular... Jun 2023Mitochondria play a key role in cancer and their involvement is not limited to the production of ATP only. Mitochondria also produce reactive oxygen species and building... (Review)
Review
Mitochondria play a key role in cancer and their involvement is not limited to the production of ATP only. Mitochondria also produce reactive oxygen species and building blocks to sustain rapid cell proliferation; thus, the deregulation of mitochondrial function is associated with cancer disease development and progression. In cancer cells, a metabolic reprogramming takes place through a different modulation of the mitochondrial metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, the Krebs cycle, glutamine and heme metabolism. Alterations of mitochondrial homeostasis, in particular, of mitochondrial biogenesis, mitophagy, dynamics, redox balance, and protein homeostasis, were also observed in cancer cells. The use of drugs acting on mitochondrial destabilization may represent a promising therapeutic approach in tumors in which mitochondrial respiration is the predominant energy source. In this review, we summarize the main mitochondrial features and metabolic pathways altered in cancer cells, moreover, we present the best known drugs that, by acting on mitochondrial homeostasis and metabolic pathways, may induce mitochondrial alterations and cancer cell death. In addition, new strategies that induce mitochondrial damage, such as photodynamic, photothermal and chemodynamic therapies, and the development of nanoformulations that specifically target drugs in mitochondria are also described. Thus, mitochondria-targeted drugs may open new frontiers to a tailored and personalized cancer therapy.
Topics: Humans; Mitochondria; Neoplasms; Oxidative Phosphorylation; Citric Acid Cycle; Oxidation-Reduction; Reactive Oxygen Species
PubMed: 37445598
DOI: 10.3390/ijms241310420 -
Current Drug Metabolism 2021In vivo biotransformation of exposed chemicals is one of the major factors that determine the concentration and the duration of a substance at the systemic site of... (Review)
Review
In vivo biotransformation of exposed chemicals is one of the major factors that determine the concentration and the duration of a substance at the systemic site of effect. Given that toxicity is expressed as a function of two factors, namely dose and time, the type and intensity of the toxicity are directly dependent on the chemical transformation of the exposed parent substance. This dependency involves two different situations. The amount of the chemical reaching the target will be decreased with the extent of metabolism if the parent chemical is toxic, and the opposite is true if the metabolite(s) is toxic instead. To date, the liver microsomal fraction in mammals has been justifiably considered as the center of biotransformation reactions because the liver and microsomes (i.e., endoplasmic reticulum component of the cell) possess the most abundant types and quantities of xenobiotic-metabolizing enzymes, especially the cytochrome P450 supergene enzyme family. These enzymes are common in all kingdoms of life, which strongly suggests that the origin of life is common. It is already known that various drugs enter mitochondria by different mechanisms, and this translocation is believed to be responsible for mitochondrial effects that are part of the therapeutic actions of various drugs such as lipid-lowering statins or antidiabetogenic thiazolidindiones. However, the discovery of mitochondrial forms of the xenobiotic-metabolizing enzymes provoked discussions about whether mitochondria metabolize drugs and other chemicals to some extent. This possibility may particularly be important as mitochondria have various critical cellular structures and functions. In the case of in situ generated metabolite(s), when there are adverse interactions with either these structures or functions, various toxic outcomes may appear. In this review, we compiled studies in the literature regarding biotransformation of drugs and other chemicals catalyzed by mitochondria where it is both an initiator and target of toxicity.
Topics: Animals; Biotransformation; Cytochrome P-450 Enzyme System; Humans; Mitochondria; Pharmaceutical Preparations; Xenobiotics
PubMed: 34182906
DOI: 10.2174/1389200222666210628125020 -
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 -
Clinical & Translational Oncology :... Oct 2020Although continuous researches are going on for the discovery of new chemotherapeutic agents, resistance to these anticancer agents has made it really difficult to reach... (Review)
Review
Although continuous researches are going on for the discovery of new chemotherapeutic agents, resistance to these anticancer agents has made it really difficult to reach the fruitful results. There are many causes for this resistance that are being studied by the researchers across the world, but still, success is far because there are several factors that are going along unattended or have been studied less. Drug-metabolizing enzymes (DMEs) are one of these factors, on which less study has been conducted. DMEs include Phase I and Phase II enzymes. Cytochrome P450s (CYPs) are major Phase I enzymes while glutathione-S-transferases (GSTs), UDP-glucuronosyltransferases (UGTs), dihydropyrimidine dehydrogenases are the major enzymes belonging to the Phase II enzymes. These enzymes play an important role in detoxification of the xenobiotics as well as the metabolism of drugs, depending upon the tissue in which they are expressed. When present in tumorous tissues, they cause resistance by metabolizing the drugs and rendering them inactive. In this review, the role of these various enzymes in anticancer drug metabolism and the possibilities for overcoming the resistance have been discussed.
Topics: Antineoplastic Agents; Catalysis; Cytochrome P-450 Enzyme System; Dihydrouracil Dehydrogenase (NADP); Drug Resistance, Neoplasm; Glucuronosyltransferase; Glutathione Transferase; Humans; Inactivation, Metabolic; Neoplasms
PubMed: 32170639
DOI: 10.1007/s12094-020-02325-7 -
Drug Metabolism Reviews Aug 2022Deoxynivalenol (DON) and its modified forms, including DON-3-glucoside (DON-3G), pose a major agricultural and food safety issue in the world. Their metabolites are... (Review)
Review
Deoxynivalenol (DON) and its modified forms, including DON-3-glucoside (DON-3G), pose a major agricultural and food safety issue in the world. Their metabolites are relatively well-characterized; however, their metabolizing enzymes have not been fully explored. UDP-glucuronosyltransferases, 3--acetyltransferase, and glutathione -transferase are involved in the formation of DON-glucuronides, 3-acetyl-DON, and DON-glutathione, respectively. There are interindividual differences in the metabolism of these toxins, including variation with respect to sex. Furthermore, interspecies differences in DON metabolism have been revealed, including differences in the major metabolites of DON, the role of de-acetylation, and the hydrolysis of DON-3G. In this review, we summarized the major enzymes involved in metabolizing DON to its modified forms, focusing on the differences in metabolism of DON and its modified forms between individuals and species. This work provides important insight into the toxicity of DON and its derivatives in humans and animals, and provides scientific basis for the development of safer and more efficient biological detoxification methods.
Topics: Animals; Glucuronides; Glucuronosyltransferase; Humans; Hydrolysis; Inactivation, Metabolic; Trichothecenes
PubMed: 35695207
DOI: 10.1080/03602532.2022.2088786 -
Biochimica Et Biophysica Acta. General... Mar 2023Our understanding of metabolic reprogramming in cancer has tremendously improved along with the technical progression of metabolomic analysis. Metabolic changes in... (Review)
Review
Our understanding of metabolic reprogramming in cancer has tremendously improved along with the technical progression of metabolomic analysis. Metabolic changes in cancer cells proved much more complicated than the classical Warburg effect. Previous studies have approached metabolic changes as therapeutic and/or chemopreventive targets. Recently, several clinical trials have reported anti-cancer agents associated with metabolism. However, whether cancer cells are dependent on metabolic reprogramming or favor suitable conditions remains nebulous. Both scenarios are possibly intertwined. Identification of downstream molecules and the understanding of mechanisms underlying reprogrammed metabolism can improve the effectiveness of cancer therapy. Here, we review several examples of the metabolic reprogramming of cancer cells and the therapies targeting the metabolism-related molecules as well as discuss practical approaches to improve the next generation of cancer therapies focused on the metabolic reprogramming of cancer.
Topics: Humans; Glycolysis; Neoplasms; Energy Metabolism; Antineoplastic Agents
PubMed: 36572257
DOI: 10.1016/j.bbagen.2022.130301 -
Current Drug Metabolism 2023Drug-metabolizing enzymes and transporters are major determinants of the absorption, disposition, metabolism, and excretion (ADME) of drugs, and changes in ADME gene... (Review)
Review
Drug-metabolizing enzymes and transporters are major determinants of the absorption, disposition, metabolism, and excretion (ADME) of drugs, and changes in ADME gene expression or function may alter the pharmacokinetics/ pharmacodynamics (PK/PD) and further influence drug safety and therapeutic outcomes. ADME gene functions are controlled by diverse factors, such as genetic polymorphism, transcriptional regulation, and coadministered medications. MicroRNAs (miRNAs) are a superfamily of regulatory small noncoding RNAs that are transcribed from the genome to regulate target gene expression at the post-transcriptional level. The roles of miRNAs in controlling ADME gene expression have been demonstrated, and such miRNAs may consequently influence cellular drug metabolism and disposition capacity. Several types of miRNA mimics and small interfering RNA (siRNA) reagents have been developed and widely used for ADME research. In this review article, we first provide a brief introduction to the mechanistic actions of miRNAs in post-transcriptional gene regulation of drug-metabolizing enzymes, transporters, and transcription factors. After summarizing conventional small RNA production methods, we highlight the latest advances in novel recombinant RNA technologies and applications of the resultant bioengineered RNA (BioRNA) agents to ADME studies. BioRNAs produced in living cells are not only powerful tools for general biological and biomedical research but also potential therapeutic agents amenable to clinical investigations.
Topics: Humans; Gene Expression Regulation; MicroRNAs; Inactivation, Metabolic
PubMed: 37170982
DOI: 10.2174/1389200224666230425232433 -
Expert Opinion on Drug Metabolism &... Jun 2024The 24-hour variations in drug absorption, distribution, metabolism, and elimination, collectively known as pharmacokinetics, are fundamentally influenced by rhythmic... (Review)
Review
INTRODUCTION
The 24-hour variations in drug absorption, distribution, metabolism, and elimination, collectively known as pharmacokinetics, are fundamentally influenced by rhythmic physiological processes regulated by the molecular clock. Recent advances have elucidated the intricacies of the circadian timing system and the molecular interplay between biological clocks, enzymes and transporters in preclinical level.
AREA COVERED
Circadian rhythm of the drug metabolizing enzymes and carrier efflux functions possess a major role for drug metabolism and detoxification. The efflux and metabolism function of intestines and liver seems important. The investigations revealed that the ABC and SLC transporter families, along with cytochrome -450 systems in the intestine, liver, and kidney, play a dominant role in the circadian detoxification of drugs. Additionally, the circadian control of efflux by the blood-brain barrier is also discussed.
EXPERT OPINION
The influence of the circadian timing system on drug pharmacokinetics significantly impacts the efficacy, adverse effects, and toxicity profiles of various drugs. Moreover, the emergence of sex-related circadian changes in the metabolism and detoxification processes has underscored the importance of considering gender-specific differences in drug tolerability and pharmacology. A better understanding of coupling between central clock and circadian metabolism/transport contributes to the development of more rational drug utilization and the implementation of chronotherapy applications.
Topics: Humans; Circadian Rhythm; Animals; Inactivation, Metabolic; Pharmaceutical Preparations; Circadian Clocks; Blood-Brain Barrier; Female; Cytochrome P-450 Enzyme System; Liver; Drug Chronotherapy; Male; Sex Factors
PubMed: 38753451
DOI: 10.1080/17425255.2024.2356167