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Drug Metabolism and Disposition: the... Dec 2023Drug-metabolizing enzymes and transporters (DMETs) are key regulators of the pharmacokinetics, efficacy, and toxicity of therapeutics. Over the past two decades,...
Drug-metabolizing enzymes and transporters (DMETs) are key regulators of the pharmacokinetics, efficacy, and toxicity of therapeutics. Over the past two decades, significant advancements in in vitro methodologies, targeted proteomics, in vitro to in vivo extrapolation methods, and integrated computational approaches such as physiologically based pharmacokinetic modeling have unequivocally contributed to improving our ability to quantitatively predict the role of DMETs in absorption, distribution, metabolism, and excretion and drug-drug interactions. However, the paucity of data regarding alterations in DMET activity in specific populations such as pregnant individuals, lactation, pediatrics, geriatrics, organ impairment, and disease states such as, cancer, kidney, and liver diseases and inflammation has restricted our ability to realize the full potential of these recent advancements. We envision that a series of carefully curated articles in a special supplementary issue of will summarize the latest progress in in silico, in vitro, and in vivo approaches to characterize alteration in DMET activity and quantitatively predict drug disposition in specific populations. In addition, the supplementary issue will underscore the current scientific knowledge gaps that present formidable barriers to fully understand the clinical implications of altered DMET activity in specific populations and highlight opportunities for multistakeholder collaboration to advance our collective understanding of this rapidly emerging area. SIGNIFICANCE STATEMENT: This commentary highlights current knowledge and identifies gaps and key challenges in understanding the role of drug-metabolizing enzymes and transporters (DMETs) in drug disposition in specific populations. With this commentary for the special issue in , the authors intend to increase interest and invite potential contributors whose research is focused or has aided in expanding the understanding around the role and impact of DMETs in drug disposition in specific populations.
Topics: Pregnancy; Female; Humans; Child; Membrane Transport Proteins; Liver Diseases; Drug Interactions; Inflammation; Metabolic Clearance Rate
PubMed: 37775331
DOI: 10.1124/dmd.123.001453 -
Cells Jan 2022Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that is activated by a variety of endogenous metabolites or xenobiotics. Its downstream target...
Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that is activated by a variety of endogenous metabolites or xenobiotics. Its downstream target genes are involved in metabolism, inflammation and processes closely related to cancer. However, the stability regulation of PXR protein resulting from post-translational modification is still largely undefined. In the present study, primary mouse hepatocytes, hepatoma HepG2 cells and HEK 293T cells were used to investigate gene expression and protein interactions. The role of kinases was evaluated by RNA interference and overexpression constructs with or without PXR phosphorylation site mutations. The activity of CYP3A4 and P-gp was determined by enzymatic and substrate accumulation assays. It was found that E3 ubiquitin ligase TRIM21 mediates the ubiquitination and degradation of PXR and plays an important role in regulating the activity of PXR. On this basis, PXR phosphorylation-associated kinases were evaluated regarding regulation of the stability of PXR. We found cyclin dependent kinase 2 (CDK2) exclusively phosphorylates PXR at Ser350, promotes its disassociation with Hsp90/DNAJC7, and leads to subsequent TRIM21-mediated PXR ubiquitination and degradation. As well-known CDK inhibitors, dinaciclib and kenpaullone stabilize PXR and result in elevated expression and activity of PXR-targeted DMETs, including carboxylesterases, CYP3A4 and P-gp. The suppressed degradation of PXR by CDK2 inhibitors denotes dinaciclib-induced promotion of PXR-targeted genes. The findings of CDK2-mediated PXR degradation indicate a wide range of potential drug-drug interactions during clinical cancer therapy using CDK inhibitors and imply an alternative direction for the development of novel PXR antagonists.
Topics: Cyclic N-Oxides; Cyclin-Dependent Kinase 2; Gene Expression Regulation; HEK293 Cells; HSP90 Heat-Shock Proteins; Heat-Shock Proteins; Hep G2 Cells; Hepatocytes; Humans; Indolizines; Molecular Chaperones; Phosphorylation; Phosphoserine; Pregnane X Receptor; Proteasome Endopeptidase Complex; Protein Binding; Protein Kinase Inhibitors; Protein Stability; Proteolysis; Pyridinium Compounds; Ribonucleoproteins; Signal Transduction; Ubiquitin; Ubiquitination
PubMed: 35053380
DOI: 10.3390/cells11020264 -
A cut above (and below): Protein cleavage in the regulation of polycystin trafficking and signaling.Cellular Signalling Aug 2020The polycystin-1 and 2 proteins, encoded by the genes mutated in Autosomal Dominant Polycystic Kidney Disease, are connected to a large number of biological pathways.... (Review)
Review
The polycystin-1 and 2 proteins, encoded by the genes mutated in Autosomal Dominant Polycystic Kidney Disease, are connected to a large number of biological pathways. While the nature of these connections and their relevance to the primary functions of the polycystin proteins have yet to be fully elucidated, it is clear that many of them are mediated by or depend upon cleavage of the polycystin-1 protein. Cleavage of polycystin-1 at its G protein coupled receptor proteolytic site is an obligate step in the protein's maturation and in aspects of its trafficking. This cleavage may also serve to prime polycystin-1 to play a role as a non-canonical G protein coupled receptor. Cleavage of the cytoplasmic polycystin-1C terminal tail releases fragments that are able to enter the nucleus and the mitochondria and to influence their activities. Understanding the nature of these cleavages, their regulation and their consequences is likely to provide valuable insights into both the physiological functions served by the polycystin proteins and the pathological consequences of their absence.
Topics: Animals; Cell Adhesion; Humans; Osteogenesis; Protein Transport; Proteolysis; Signal Transduction; TRPP Cation Channels
PubMed: 32283256
DOI: 10.1016/j.cellsig.2020.109634 -
International Journal of Molecular... Dec 2022Despite numerous therapies, cancer remains one of the leading causes of death worldwide due to the lack of markers for early detection and response to treatment in many... (Review)
Review
Despite numerous therapies, cancer remains one of the leading causes of death worldwide due to the lack of markers for early detection and response to treatment in many patients. Technological advances in tumor screening and renewed interest in energy metabolism have allowed us to identify new cellular players in order to develop personalized treatments. Among the metabolic actors, the mitochondrial transporter uncoupling protein 2 (UCP2), whose expression is increased in many cancers, has been identified as an interesting target in tumor metabolic reprogramming. Over the past decade, a better understanding of its biochemical and physiological functions has established a role for UCP2 in (1) protecting cells from oxidative stress, (2) regulating tumor progression through changes in glycolytic, oxidative and calcium metabolism, and (3) increasing antitumor immunity in the tumor microenvironment to limit cancer development. With these pleiotropic roles, UCP2 can be considered as a potential tumor biomarker that may be interesting to target positively or negatively, depending on the type, metabolic status and stage of tumors, in combination with conventional chemotherapy or immunotherapy to control tumor development and increase response to treatment. This review provides an overview of the latest published science linking mitochondrial UCP2 activity to the tumor context.
Topics: Humans; Uncoupling Protein 2; Oxidative Stress; Energy Metabolism; Oxidation-Reduction; Neoplasms; Mitochondrial Proteins; Reactive Oxygen Species; Tumor Microenvironment
PubMed: 36499405
DOI: 10.3390/ijms232315077 -
Food & Function Oct 2023The synthesis and metabolism of bile acids (BAs) have been implicated in various metabolic diseases, including obesity and diabetes. Dietary polyphenols, as natural... (Review)
Review
The synthesis and metabolism of bile acids (BAs) have been implicated in various metabolic diseases, including obesity and diabetes. Dietary polyphenols, as natural antioxidants, play a vital role in synthesizing and metabolizing bile acids. This paper reviews the mechanism of dietary polyphenols involved in bile acid (BA) synthesis and metabolism. The impact of different gut microorganisms on BA profiles is discussed in detail. The regulation of BA metabolism by dietary polyphenols can be divided into two modes: (1) dietary polyphenols directly activate/inhibit farnesol X receptor (FXR) and Takeda G protein-coupled receptor (TGR5); (2) dietary polyphenols regulate BA synthesis and metabolism through changes in intestinal microorganisms. Research on direct activation/inhibition of FXR and TGR5 by polyphenols should be ramped up. In addition, the effect of dietary polyphenols on intestinal microorganisms has been paid more and more attention and has become a target that cannot be ignored.
Topics: Humans; Bile Acids and Salts; Receptors, G-Protein-Coupled; Obesity; Lipid Metabolism; Homeostasis
PubMed: 37815149
DOI: 10.1039/d3fo02471g -
Cells Feb 2022Unresolved hyperglycaemia, a hallmark of type 2 diabetes mellitus (T2DM), is a well characterised manifestation of altered fuel homeostasis and our understanding of its... (Review)
Review
Unresolved hyperglycaemia, a hallmark of type 2 diabetes mellitus (T2DM), is a well characterised manifestation of altered fuel homeostasis and our understanding of its role in the pathologic activation of the inflammatory system continues to grow. Metabolic disorders like T2DM trigger changes in the regulation of key cellular processes such as cell trafficking and proliferation, and manifest as chronic inflammatory disorders with severe long-term consequences. Activation of inflammatory pathways has recently emerged as a critical link between T2DM and inflammation. A substantial body of evidence has suggested that this is due in part to increased flux through the hexosamine biosynthetic pathway (HBP). The HBP, a unique nutrient-sensing metabolic pathway, produces the activated amino sugar UDP-GlcNAc which is a critical substrate for protein -GlcNAcylation, a dynamic, reversible post-translational glycosylation of serine and threonine residues in target proteins. Protein -GlcNAcylation impacts a range of cellular processes, including inflammation, metabolism, trafficking, and cytoskeletal organisation. As increased HBP flux culminates in increased protein -GlcNAcylation, we propose that targeting -GlcNAcylation may be a viable therapeutic strategy for the prevention and management of glucose-dependent pathologies with inflammatory components.
Topics: Diabetes Mellitus, Type 2; Glycosylation; Hexosamines; Humans; Inflammation; Protein Processing, Post-Translational; Proteins
PubMed: 35203353
DOI: 10.3390/cells11040705 -
Trends in Endocrinology and Metabolism:... Feb 2021β-Arrestin-1 and -2 are intracellular proteins that are able to inhibit signaling via G protein-coupled receptors (GPCRs). However, both proteins can also modulate... (Review)
Review
β-Arrestin-1 and -2 are intracellular proteins that are able to inhibit signaling via G protein-coupled receptors (GPCRs). However, both proteins can also modulate cellular functions in a G protein-independent fashion. During the past few years, studies with mutant mice selectivity lacking β-arrestin-1 and/or -2 in metabolically important cell types have led to novel insights into the mechanisms through which β-arrestins regulate key metabolic processes in vivo, including whole-body glucose and energy homeostasis. The novel information gained from these studies should inform the development of novel drugs, including β-arrestin- or G protein-biased GPCR ligands, that could prove useful for the therapy of several important pathophysiological conditions, including type 2 diabetes and obesity.
Topics: Animals; Humans; Mice; Protein Binding; Receptors, G-Protein-Coupled; Signal Transduction; beta-Arrestins
PubMed: 33358450
DOI: 10.1016/j.tem.2020.11.008 -
Computers in Biology and Medicine Sep 2023S-sulfenylation is a vital post-translational modification (PTM) of proteins, which is an intermediate in other redox reactions and has implications for signal...
S-sulfenylation is a vital post-translational modification (PTM) of proteins, which is an intermediate in other redox reactions and has implications for signal transduction and protein function regulation. However, there are many restrictions on the experimental identification of S-sulfenylation sites. Therefore, predicting S-sulfoylation sites by computational methods is fundamental to studying protein function and related biological mechanisms. In this paper, we propose a method named BiGRUD-SA based on bi-directional gated recurrent unit (BiGRU) and self-attention mechanism to predict protein S-sulfenylation sites. We first use AAC, BLOSUM62, AAindex, EAAC and GAAC to extract features, and do feature fusion to obtain original feature space. Next, we use SMOTE-Tomek method to handle data imbalance. Then, we input the processed data to the BiGRU and use self-attention mechanism to do further feature extraction. Finally, we input the data obtained to the deep neural networks (DNN) to identify S-sulfenylation sites. The accuracies of training set and independent test set are 96.66% and 95.91% respectively, which indicates that our method is conducive to identifying S-sulfenylation sites. Furthermore, we use a data set of S-sulfenylation sites in Arabidopsis thaliana to effectively verify the generalization ability of BiGRUD-SA method, and obtain better prediction results.
Topics: Protein S; Computational Biology; Support Vector Machine; Proteins; Protein Processing, Post-Translational; Arabidopsis
PubMed: 37336062
DOI: 10.1016/j.compbiomed.2023.107145 -
Biochimica Et Biophysica Acta.... Jun 2021Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two nuclear receptors that are well-known for their roles in xenobiotic detoxification by... (Review)
Review
Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two nuclear receptors that are well-known for their roles in xenobiotic detoxification by regulating the expression of drug-metabolizing enzymes and transporters. In addition to metabolizing drugs and other xenobiotics, the same enzymes and transporters are also responsible for the production and elimination of numerous endogenous chemicals, or endobiotics. Moreover, both PXR and CAR are highly expressed in the liver. As such, it is conceivable that PXR and CAR have major potentials to affect the pathophysiology of the liver by regulating the homeostasis of endobiotics. In recent years, the physiological functions of PXR and CAR in the liver have been extensively studied. Emerging evidence has suggested the roles of PXR and CAR in energy metabolism, bile acid homeostasis, cell proliferation, to name a few. This review summarizes the recent progress in our understanding of the roles of PXR and CAR in liver physiology.
Topics: Animals; Constitutive Androstane Receptor; Humans; Inactivation, Metabolic; Liver Diseases; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Xenobiotics
PubMed: 33600998
DOI: 10.1016/j.bbadis.2021.166101 -
Molecular and Cellular Biochemistry Apr 2022Imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and asciminib are FDA-approved tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML), each of which... (Review)
Review
Imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and asciminib are FDA-approved tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML), each of which has a specific pharmacological profile. Asciminib has been recently (2021) approved for patients resistant to former TKIs, and because the binding site of this drug (the myristoyl pocket in the ABL1 kinase) is different from that of other TKIs (ATP-binding sites), it is, therefore, effective against T315I mutation of BCR-ABL oncoprotein. All TKIs have a different pharmacological profile due to different chemical structures. Imatinib is the only TKI whose absorption depends on both influx (OCT1 and OATP1A2) and efflux (ABCB1 and ABCG2) transporters, whereas the others rely only on efflux transporters. The efflux of dasatinib is also regulated by ABCC4 and ABCC6 transporters. Nilotinib and ponatinib are transported passively, as no role of transporters has been found in their case. A phenomenon common to all in the metabolic aspect is that the CYP3A4 isoform of CYP450 primarily metabolizes TKIs. Not only does CYP3A4, flavin-containing monooxygenase 3 (FMO3), and uridine 5'-diphospho-glucuronosyltransferase (UGT) also metabolize dasatinib, and similarly, by glucuronidation process, asciminib gets metabolized by UGT enzymes (UGT1A3, UGT1A4, UGT2B7, and UGT2B17). Additionally, the side effects of TKIs are categorized as hematological (thrombocytopenia, neutropenia, anemia, and cardiac dysfunction) and non-hematological (diarrhea, nausea, vomiting, pleural effusion, and skin rash). However, few toxicities are drug-specific, like degradation of biomolecules by ponatinib-glutathione (P-GSH) conjugates and clinical pancreatitis (dose-limited toxicity and manageable by dosage alterations) are related to ponatinib and asciminib, respectively. This review focuses on the pharmacokinetics of approved TKIs related to CML therapy to comprehend their specificity, tolerability, and off-target effects, which could help clinicians to make a patient-specific selection of CML drugs by considering concomitant diseases and risk factors to the patients.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasm Proteins; Protein Kinase Inhibitors
PubMed: 35129779
DOI: 10.1007/s11010-022-04376-6