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International Journal of Molecular... Nov 2021Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In... (Review)
Review
Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1-3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy.
Topics: Animals; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Pharmaceutical Preparations; Polymorphism, Genetic; Xenobiotics
PubMed: 34884615
DOI: 10.3390/ijms222312808 -
Microbial Ecology Jul 2023The efficacy of drugs widely varies in individuals, and the gut microbiota plays an important role in this variability. The commensal microbiota living in the human gut... (Review)
Review
The efficacy of drugs widely varies in individuals, and the gut microbiota plays an important role in this variability. The commensal microbiota living in the human gut encodes several enzymes that chemically modify systemic and orally administered drugs, and such modifications can lead to activation, inactivation, toxification, altered stability, poor bioavailability, and rapid excretion. Our knowledge of the role of the human gut microbiome in therapeutic outcomes continues to evolve. Recent studies suggest the existence of complex interactions between microbial functions and therapeutic drugs across the human body. Therapeutic drugs or xenobiotics can influence the composition of the gut microbiome and the microbial encoded functions. Both these deviations can alter the chemical transformations of the drugs and hence treatment outcomes. In this review, we provide an overview of (i) the genetic ecology of microbially encoded functions linked with xenobiotic degradation; (ii) the effect of drugs on the composition and function of the gut microbiome; and (iii) the importance of the gut microbiota in drug metabolism.
Topics: Humans; Gastrointestinal Microbiome; Microbiota; Xenobiotics
PubMed: 35869999
DOI: 10.1007/s00248-022-02081-x -
Pharmacology & Therapeutics Dec 2018Drug transporter proteins are critical to the distribution of a wide range of endogenous compounds and xenobiotics such as hormones, bile acids, peptides, lipids,... (Review)
Review
Drug transporter proteins are critical to the distribution of a wide range of endogenous compounds and xenobiotics such as hormones, bile acids, peptides, lipids, sugars, and drugs. There are two classes of drug transporters- the solute carrier (SLC) transporters and ATP-binding cassette (ABC) transporters -which predominantly differ in the energy source utilized to transport substrates across a membrane barrier. Despite their hydrophobic nature and residence in the membrane bilayer, drug transporters have dynamic structures and adopt many conformations during the translocation process. Whereas there is significant literature evidence for the substrate specificity and structure-function relationship for clinically relevant drug transporters proteins, there is less of an understanding in the regulatory mechanisms that contribute to the functional expression of these proteins. Post-translational modifications have been shown to modulate drug transporter functional expression via a wide range of molecular mechanisms. These modifications commonly occur through the addition of a functional group (e.g. phosphorylation), a small protein (e.g. ubiquitination), sugar chains (e.g. glycosylation), or lipids (e.g. palmitoylation) on solvent accessible amino acid residues. These covalent additions often occur as a result of a signaling cascade and may be reversible depending on the type of modification and the intended fate of the signaling event. Here, we review the significant role in which post-translational modifications contribute to the dynamic regulation and functional consequences of SLC and ABC drug transporters and highlight recent progress in understanding their roles in transporter structure, function, and regulation.
Topics: ATP-Binding Cassette Transporters; Animals; Biological Transport; Glycosylation; Humans; Pharmaceutical Preparations; Phosphorylation; Protein Processing, Post-Translational; Solute Carrier Proteins; Ubiquitination; Xenobiotics
PubMed: 29966598
DOI: 10.1016/j.pharmthera.2018.06.013 -
Science (New York, N.Y.) Jun 2017The human gut microbiota makes key contributions to the metabolism of ingested compounds (xenobiotics), transforming hundreds of dietary components, industrial... (Review)
Review
The human gut microbiota makes key contributions to the metabolism of ingested compounds (xenobiotics), transforming hundreds of dietary components, industrial chemicals, and pharmaceuticals into metabolites with altered activities, toxicities, and lifetimes within the body. The chemistry of gut microbial xenobiotic metabolism is often distinct from that of host enzymes. Despite their important consequences for human biology, the gut microbes, genes, and enzymes involved in xenobiotic metabolism are poorly understood. Linking these microbial transformations to enzymes and elucidating their biological effects is undoubtedly challenging. However, recent studies demonstrate that integrating traditional and emerging technologies can enable progress toward this goal. Ultimately, a molecular understanding of gut microbial xenobiotic metabolism will guide personalized medicine and nutrition, inform toxicology risk assessment, and improve drug discovery and development.
Topics: Bacteria; Environmental Pollutants; Food; Gastrointestinal Microbiome; Humans; Pharmaceutical Preparations; Research; Xenobiotics
PubMed: 28642381
DOI: 10.1126/science.aag2770 -
The Journal of Biological Chemistry Jan 2020Cytochrome P450 enzymes (P450s) are broadly distributed among living organisms and play crucial roles in natural product biosynthesis, degradation of xenobiotics,... (Review)
Review
Cytochrome P450 enzymes (P450s) are broadly distributed among living organisms and play crucial roles in natural product biosynthesis, degradation of xenobiotics, steroid biosynthesis, and drug metabolism. P450s are considered as the most versatile biocatalysts in nature because of the vast variety of substrate structures and the types of reactions they catalyze. In particular, P450s can catalyze regio- and stereoselective oxidations of nonactivated C-H bonds in complex organic molecules under mild conditions, making P450s useful biocatalysts in the production of commodity pharmaceuticals, fine or bulk chemicals, bioremediation agents, flavors, and fragrances. Major efforts have been made in engineering improved P450 systems that overcome the inherent limitations of the native enzymes. In this review, we focus on recent progress of different strategies, including protein engineering, redox-partner engineering, substrate engineering, electron source engineering, and P450-mediated metabolic engineering, in efforts to more efficiently produce pharmaceuticals and other chemicals. We also discuss future opportunities for engineering and applications of the P450 systems.
Topics: Biocatalysis; Biotechnology; Cytochrome P-450 Enzyme System; Metabolic Engineering; Protein Engineering; Steroids; Substrate Specificity; Xenobiotics
PubMed: 31811088
DOI: 10.1074/jbc.REV119.008758 -
Nature Reviews. Drug Discovery Aug 2015Solute carrier (SLC) transporters - a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological... (Review)
Review
Solute carrier (SLC) transporters - a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes - have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets.
Topics: Animals; Biological Transport; Drug Design; Drugs, Investigational; Humans; Membrane Transport Proteins; Molecular Targeted Therapy; Xenobiotics
PubMed: 26111766
DOI: 10.1038/nrd4626 -
JCI Insight Oct 2017Our goal was to identify changes in the metabolome in multiple sclerosis (MS) and how vitamin D supplementation alters metabolic profiles in MS patients and healthy... (Clinical Trial)
Clinical Trial
BACKGROUND
Our goal was to identify changes in the metabolome in multiple sclerosis (MS) and how vitamin D supplementation alters metabolic profiles in MS patients and healthy controls.
METHODS
We applied global untargeted metabolomics to plasma from a cross-sectional cohort of age- and sex-matched MS patients and controls and a second longitudinal cohort of MS patients and healthy controls who received 5,000 IU cholecalciferol daily for 90 days. We applied partial least squares discriminant analysis, weighted correlation network analysis (WGCNA), and pathway analysis to the metabolomics data. Generalized estimating equations models were used to assess change in WGCNA-identified module scores or metabolite pathways with vitamin D supplementation.
RESULTS
Utilizing multiple analytical techniques, we identified metabolic alterations in oxidative stress (γ-glutamyl amino acid, glutathione) and xenobiotic metabolism (benzoate, caffeine) in MS patients compared with healthy controls in the first cohort. In the vitamin D supplementation cohort, we identified two sets of metabolites altered differentially between MS patients and healthy controls with vitamin D supplementation. The first included markers of oxidative stress and protein oxidation (P = 0.006), while the second contained lysolipids and fatty acids (P = 0.03).
CONCLUSIONS
Using metabolomics, we identified alterations in oxidative stress and xenobiotic metabolism in MS patients and subsequently demonstrated a reduction of oxidative stress markers with vitamin D supplementation in healthy controls but not in MS patients. We demonstrate the utility of metabolomics in identifying aberrant metabolic processes and in monitoring the ability of therapeutic interventions to correct these abnormalities.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01667796.
FUNDING
This study was supported by NIH grant K23 NS067055, grants from the Race to Erase MS, the National Multiple Sclerosis Society, the American Academy of Neurology, and North American Research Committee on Multiple Sclerosis.
Topics: Adult; Case-Control Studies; Cholecalciferol; Cross-Sectional Studies; Dietary Supplements; Female; Humans; Metabolome; Metabolomics; Middle Aged; Multiple Sclerosis; Oxidative Stress; Xenobiotics
PubMed: 28978801
DOI: 10.1172/jci.insight.95302 -
Critical Care (London, England) Jul 2012In order to assess the significance of drug levels measured in intensive care medicine, clinical and forensic toxicology, as well as for therapeutic drug monitoring, it... (Review)
Review
INTRODUCTION
In order to assess the significance of drug levels measured in intensive care medicine, clinical and forensic toxicology, as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. Therefore, it makes sense to offer a carefully referenced compilation of therapeutic and toxic plasma concentration ranges, as well as half-lives, of a large number of drugs and other xenobiotics for quick and comprehensive information.
METHODS
Data have been abstracted from original papers and text books, as well as from previous compilations, and have been completed with data collected in our own forensic and clinical toxicology laboratory. The data presented in the table and corresponding annotations have been developed over the past 20 years and longer. A previous compilation has been completely revised and updated. In addition, more than 170 substances, especially drugs that have been introduced to the market since 2003 as well as illegal drugs, which became known to cause intoxications, were added. All data were carefully referenced and more than 200 new references were included. Moreover, the annotations providing details were completely revised and more than 100 annotations were added.
RESULTS
For nearly 1,000 drugs and other xenobiotics, therapeutic ("normal") and, if data were available, toxic and comatose-fatal blood-plasma concentrations and elimination half-lives were compiled in a table.
CONCLUSIONS
In case of intoxications, the concentration of the ingested substances and/or metabolites in blood plasma better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment and monitoring of acute and chronic intoxications, and to support forensic and clinical expert opinions.
Topics: Critical Care; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Humans; Xenobiotics
PubMed: 22835221
DOI: 10.1186/cc11441 -
Journal of Toxicology and Environmental... Feb 2021has emerged as a major model in biomedical and environmental toxicology. Numerous papers on toxicology and pharmacology in have been published, and this species has... (Review)
Review
has emerged as a major model in biomedical and environmental toxicology. Numerous papers on toxicology and pharmacology in have been published, and this species has now been adopted by investigators in academic toxicology, pharmacology, and drug discovery labs. has also attracted the interest of governmental regulatory agencies charged with evaluating the safety of chemicals. However, a major, fundamental aspect of toxicological science remains underdeveloped in : xenobiotic metabolism and transport processes that are critical to understanding toxicokinetics and toxicodynamics, and extrapolation to other species. The aim of this review was to initially briefly describe the history and trajectory of the use of in toxicological and pharmacological studies. Subsequently, physical barriers to chemical uptake and the role of the worm microbiome in xenobiotic transformation were described. Then a review of what is and is not known regarding the classic Phase I, Phase II, and Phase III processes was performed. In addition, the following were discussed (1) regulation of xenobiotic metabolism; (2) review of published toxicokinetics for specific chemicals; and (3) genetic diversity of these processes in . Finally, worm xenobiotic transport and metabolism was placed in an evolutionary context; key areas for future research highlighted; and implications for extrapolating toxicity results to other species discussed.
Topics: Animals; Biological Transport; Caenorhabditis elegans; Ecotoxicology; Humans; Models, Animal; Pharmaceutical Preparations; Species Specificity; Toxicology; Xenobiotics
PubMed: 33616007
DOI: 10.1080/10937404.2021.1884921 -
Chemical Research in Toxicology Jul 2022The understanding of how exogenous chemicals (xenobiotics) are metabolized, distributed, and eliminated is critical to determine the impact of the chemical and its... (Review)
Review
The understanding of how exogenous chemicals (xenobiotics) are metabolized, distributed, and eliminated is critical to determine the impact of the chemical and its metabolites to the (human) organism. This is part of the research and educational discipline ADMET (absorption, distribution, metabolism, elimination, and toxicity). Here, we review the work of Jan Commandeur and colleagues who have not only made a significant impact in understanding of phase I and phase II metabolism of several important compounds but also contributed greatly to the development of experimental techniques for the study of xenobiotic metabolism. Jan Commandeur's work has covered a broad area of research, such as the development of online screening methodologies, the use of a combination of enzyme mutagenesis and molecular modeling for structure-activity relationship (SAR) studies, and the development of novel probe substrates. This work is the bedrock of current activities and brings the field closer to personalized (cohort-based) pharmacology, toxicology, and hazard/risk assessment.
Topics: Humans; Inactivation, Metabolic; Xenobiotics
PubMed: 35768066
DOI: 10.1021/acs.chemrestox.2c00067