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Journal of Personalized Medicine Aug 2022Genetic variability in CYP2C19 may be associated with both lack of efficacy and toxicity of drugs due to its different metabolic status based on the presence of... (Review)
Review
Genetic variability in CYP2C19 may be associated with both lack of efficacy and toxicity of drugs due to its different metabolic status based on the presence of particular alleles. This literature review summarizes current knowledge relative to the association or treatment adaptation based on genetics in a pediatric population receiving drugs metabolized by CYP2C19, such as voriconazole, antidepressants, clopidogrel and proton pump inhibitors. Additionally, we also presented one of the approaches that we developed for detection of variant alleles in the CYP2C19 gene. A total of 25 articles on PubMed were retained for the study. All studies included pediatric patients (age up to 21 years) having benefited from an assessment of CYP2C19. CYP2C19 poor and intermediate metabolizers exhibit a higher trough plasma concentration of voriconazole, and PPIs compared to the rapid and ultra-rapid metabolizers. The pharmacogenetic data relative to CYP2C19 and clopidogrel in the pediatric population are not yet available. CYP2C19 poor metabolizers have a higher trough plasma concentration of antidepressants compared to the rapid and the ultra-rapid metabolizers. Modification of allele-specific PCR through the introduction of artificial mismatch is presented. CYP2C19 genotyping remains a powerful tool needed to optimize the treatment of children receiving voriconazole, PPIs, and anti-depressants.
PubMed: 36143168
DOI: 10.3390/jpm12091383 -
Expert Opinion on Drug Metabolism &... Feb 2011It has been known for a long time that the efficiency and toxicity of drugs change during a 24-h period. However, the molecular mechanisms involved in these processes... (Review)
Review
INTRODUCTION
It has been known for a long time that the efficiency and toxicity of drugs change during a 24-h period. However, the molecular mechanisms involved in these processes have started to emerge only recently.
AREAS COVERED
This review aims to highlight recent discoveries showing the direct role of the molecular circadian clock in xenobiotic metabolism at the transcriptional and post-transcriptional levels in the liver and intestine, and the different ways of elimination of these metabolized drugs via biliary and urine excretions. Most of the related literature focuses on transcriptional regulation by the circadian clock of xenobiotic metabolism in the liver; however, the role of this timing system in the excretion of metabolized drugs and the importance of the kidney in this phenomenon are generally neglected. The goal of this review is to describe the molecular mechanisms involved in rhythmic drug metabolism and excretion.
EXPERT OPINION
Chronopharmacology is used to analyze the metabolism of drugs in mammals according to the time of day. The circadian timing system plays a key role in the changes of toxicity of drugs by influencing their metabolisms in the liver and intestine in addition to their excretion via bile flow and urine.
Topics: Animals; Bile; Biliary Tract; Circadian Clocks; Circadian Rhythm; Gene Expression Regulation; Humans; Inactivation, Metabolic; Kidney; Liver; Mammals; Pharmaceutical Preparations; Time Factors
PubMed: 21192771
DOI: 10.1517/17425255.2011.544251 -
Journal of Molecular Evolution Sep 2020The emergence of cellular organisms occurred sometime between the origin of life and the evolution of the last universal common ancestor and represents one of the major...
The emergence of cellular organisms occurred sometime between the origin of life and the evolution of the last universal common ancestor and represents one of the major transitions in evolutionary history. Here we describe a series of artificial life simulations that reveal a close relationship between the evolution of cellularity, the evolution of metabolism, and the richness of the environment. When environments are rich in processing energy, a resource that the digital organisms require to both process their genomes and replicate, populations evolve toward a state of non-cellularity. But when processing energy is not readily available in the environment and organisms must produce their own processing energy from food puzzles, populations always evolve both a proficient metabolism and a high level of cellular impermeability. Even between these two environmental extremes, the population-averaged values of cellular impermeability and metabolic proficiency exhibit a very strong correlation with one another. Further investigations show that non-cellularity is selectively advantageous when environmental processing energy is abundant because it allows organisms to access the available energy, while cellularity is selectively advantageous when environmental processing energy is scarce because it affords organisms the genetic fidelity required to incrementally evolve efficient metabolisms. The selection pressures favoring either non-cellularity or cellularity can be reversed when the environment transitions from one of abundant processing energy to one of scarce processing energy. These results have important implications for when and why cellular organisms evolved following the origin of life.
Topics: Biological Evolution; Cell Biology; Cells; Computer Simulation; Evolution, Molecular; Metabolism; Models, Biological; Origin of Life
PubMed: 32809045
DOI: 10.1007/s00239-020-09961-1 -
BioMed Research International 2013Succinate is a promising chemical which has wide applications and can be produced by biological route. The history of the biosuccinate production shows that the joint... (Review)
Review
Succinate is a promising chemical which has wide applications and can be produced by biological route. The history of the biosuccinate production shows that the joint effort of different metabolic engineering approaches brings successful results. In order to enhance the succinate production, multiple metabolical strategies have been sought. In this review, different overproducers for succinate production, including natural succinate overproducers and metabolic engineered overproducers, are examined and the metabolic engineering strategies and performances are discussed. Modification of the mechanism of substrate transportation, knocking-out genes responsible for by-products accumulation, overexpression of the genes directly involved in the pathway, and improvement of internal NADH and ATP formation are some of the strategies applied. Combination of the appropriate genes from homologous and heterologous hosts, extension of substrate, integrated production of succinate, and other high-value-added products are expected to bring a desired objective of producing succinate from renewable resources economically and efficiently.
Topics: Biological Transport; Genetic Engineering; Metabolic Engineering; Metabolic Networks and Pathways; Succinic Acid
PubMed: 23691505
DOI: 10.1155/2013/538790 -
PloS One 2016Humans are exposed to numerous xenobiotics, a majority of which are in the form of pharmaceuticals. Apart from human enzymes, recent studies have indicated the role of...
Humans are exposed to numerous xenobiotics, a majority of which are in the form of pharmaceuticals. Apart from human enzymes, recent studies have indicated the role of the gut bacterial community (microbiome) in metabolizing xenobiotics. However, little is known about the contribution of the plethora of gut microbiome in xenobiotic metabolism. The present study reports the results of analyses on xenobiotic metabolizing enzymes in various human gut microbiomes. A total of 397 available gut metagenomes from individuals of varying age groups from 8 nationalities were analyzed. Based on the diversities and abundances of the xenobiotic metabolizing enzymes, various bacterial taxa were classified into three groups, namely, least versatile, intermediately versatile and highly versatile xenobiotic metabolizers. Most interestingly, specific relationships were observed between the overall drug consumption profile and the abundance and diversity of the xenobiotic metabolizing repertoire in various geographies. The obtained differential abundance patterns of xenobiotic metabolizing enzymes and bacterial genera harboring them, suggest their links to pharmacokinetic variations among individuals. Additional analyses of a few well studied classes of drug modifying enzymes (DMEs) also indicate geographic as well as age specific trends.
Topics: Adolescent; Adult; Age Factors; Aged; Bacteria; Child; Child, Preschool; Enzymes; Ethnicity; Female; Gastrointestinal Microbiome; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Enzymologic; Humans; Inactivation, Metabolic; Infant; Infant, Newborn; Male; Metabolic Networks and Pathways; Metagenome; Middle Aged; Xenobiotics
PubMed: 27695034
DOI: 10.1371/journal.pone.0163099 -
Biochimica Et Biophysica Acta Feb 2013Although at low concentrations, arsenic commonly occurs naturally as a local geological constituent. Whereas both arsenate and arsenite are strongly toxic to life, a... (Review)
Review
Although at low concentrations, arsenic commonly occurs naturally as a local geological constituent. Whereas both arsenate and arsenite are strongly toxic to life, a number of prokaryotes use these compounds as electron acceptors or donors, respectively, for bioenergetic purposes via respiratory arsenate reductase, arsenite oxidase and alternative arsenite oxidase. The recent burst in discovered arsenite oxidizing and arsenate respiring microbes suggests the arsenic bioenergetic metabolisms to be anything but exotic. The first goal of the present review is to bring to light the widespread distribution and diversity of these metabolizing pathways. The second goal is to present an evolutionary analysis of these diverse energetic pathways. Taking into account not only the available data on the arsenic metabolizing enzymes and their phylogenetical relatives but also the palaeogeochemical records, we propose a crucial role of arsenite oxidation via arsenite oxidase in primordial life. This article is part of a Special Issue entitled: The evolutionary aspects of bioenergetic systems.
Topics: Alcaligenes faecalis; Arsenate Reductases; Arsenic; Energy Metabolism; Oxidation-Reduction; Oxidoreductases; Protein Conformation
PubMed: 22982475
DOI: 10.1016/j.bbabio.2012.08.007 -
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 -
PloS One 2016The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or...
The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). DDC is metabolized mainly by cytochrome P450 (Cyp)3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC.
Topics: Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Female; Gene Expression Regulation; Liver; Male; Mice; Oxidative Stress; Protoporphyrins; Pyridines; Retinoblastoma Protein; Tumor Suppressor Protein p53
PubMed: 26967735
DOI: 10.1371/journal.pone.0150064 -
Trends in Endocrinology and Metabolism:... Jul 2014Metabolic homeostasis is achieved through coordinated regulation across several tissues. Studies using mouse genetic models have shown that perturbation of specific... (Review)
Review
Metabolic homeostasis is achieved through coordinated regulation across several tissues. Studies using mouse genetic models have shown that perturbation of specific pathways of lipid metabolism in metabolically active tissues impacts systemic metabolic homeostasis. The use of metabolomic technologies combined with genetic models has helped to identify several potential lipid mediators that serve as metabolic messengers to communicate energy status and modulate substrate utilization among tissues. When provided exogenously, these lipid metabolites exhibit biological effects on glucose and lipid metabolism, indicating a therapeutic potential for treating metabolic diseases. In this review we summarize recent advances in inter-organ communication through novel mechanisms, with a focus on lipid mediators synthesized de novo or derived from dietary sources, and discuss challenges and future directions.
Topics: Animals; Energy Metabolism; Glucose; Humans; Lipid Metabolism; T-Lymphocytes, Regulatory
PubMed: 24895003
DOI: 10.1016/j.tem.2014.05.002 -
Drug Metabolism and Disposition: the... Aug 2015The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014...
The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014 Experimental Biology meeting in San Diego is summarized in this report. Emerging evidence has demonstrated that drug-metabolizing enzyme and transporter activity at the site of therapeutic action can affect the efficacy, safety, and metabolic properties of a given drug, with potential outcomes including altered dosing regimens, stricter exclusion criteria, or even the failure of a new chemical entity in clinical trials. Drug metabolism within the brain, for example, can contribute to metabolic activation of therapeutic drugs such as codeine as well as the elimination of potential neurotoxins in the brain. Similarly, the activity of oxidative and conjugative drug-metabolizing enzymes in the lung can have an effect on the efficacy of compounds such as resveratrol. In addition to metabolism, the active transport of compounds into or away from the site of action can also influence the outcome of a given therapeutic regimen or disease progression. For example, organic anion transporter 3 is involved in the initiation of pancreatic β-cell dysfunction and may have a role in how uremic toxins enter pancreatic β-cells and ultimately contribute to the pathogenesis of gestational diabetes. Finally, it is likely that a combination of target-specific metabolism and cellular internalization may have a significant role in determining the pharmacokinetics and efficacy of antibody-drug conjugates, a finding which has resulted in the development of a host of new analytical methods that are now used for characterizing the metabolism and disposition of antibody-drug conjugates. Taken together, the research summarized herein can provide for an increased understanding of potential barriers to drug efficacy and allow for a more rational approach for developing safe and effective therapeutics.
Topics: Animals; Biological Transport; Biological Transport, Active; Drug Delivery Systems; Humans; Inactivation, Metabolic; Pharmaceutical Preparations
PubMed: 25986849
DOI: 10.1124/dmd.115.064576