Epigenetics in drug disposition &amp; drug therapy: symposium report of the 24<sup>th</sup> North American meeting of the International Society for the Study of Xenobiotics (ISSX)

Maldonato, Benjamin J.; Vergara, Ana G.; Yadav, Jaydeep; Glass, Sarah M.; Paragas, Erickson M.; Li, Dongying; Lazarus, Philip; McClay, Joseph L.; Daly, Ann K.; Russell, Lauren

doi:10.1080/03602532.2022.2101662

Cited by 3 publications

(6 citation statements)

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“…Concerning XMPs, which are the focus of this review, it was shown that epigenetic mechanisms can influence the expression of XMP genes [ 58 , 59 ]. One of the best described cases is that of the long-term effect of the Constitutive Androstane Receptor (CAR) ligand TCPOBOP.…”

Section: Long-term Adaptation and Epigeneticsmentioning

confidence: 99%

Costs of molecular adaptation to the chemical exposome: a focus on xenobiotic metabolism pathways

Tomkiewicz,

Coumoul,

Nioche

et al. 2024

Phil. Trans. R. Soc. B

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Organisms adapt to their environment through different pathways. In vertebrates, xenobiotics are detected, metabolized and eliminated through the inducible xenobiotic-metabolizing pathways (XMP) which can also generate reactive toxic intermediates. In this review, we will discuss the impacts of the chemical exposome complexity on the balance between detoxication and side effects. There is a large discrepancy between the limited number of proteins involved in these pathways (few dozens) and the diversity and complexity of the chemical exposome (tens of thousands of chemicals). Several XMP proteins have a low specificity which allows them to bind and/or metabolize a large number of chemicals. This leads to undesired consequences, such as cross-inhibition, inefficient metabolism, release of toxic intermediates, etc. Furthermore, several XMP proteins have endogenous functions that may be disrupted upon exposure to exogenous chemicals. The gut microbiome produces a very large number of metabolites that enter the body and are part of the chemical exposome. It can metabolize xenobiotics and either eliminate them or lead to toxic derivatives. The complex interactions between chemicals of different origins will be illustrated by the diverse roles of the aryl hydrocarbon receptor which binds and transduces the signals of a large number of xenobiotics, microbiome metabolites, dietary chemicals and endogenous compounds. This article is part of the theme issue ‘Endocrine responses to environmental variation: conceptual approaches and recent developments’.

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Section: Long-term Adaptation and Epigeneticsmentioning

confidence: 99%

Costs of molecular adaptation to the chemical exposome: a focus on xenobiotic metabolism pathways

Tomkiewicz,

Coumoul,

Nioche

et al. 2024

Phil. Trans. R. Soc. B

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“…As noted earlier, epigenetic regulation can influence DME expression ( Ivanov et al, 2012 ; Kacevska et al, 2012 ; Klein and Zanger, 2013 ; Zhong and Leeder, 2013 ; Zanger et al, 2014 ). Epigenetic regulation refers to heritable genomic modifications that do not involve altering the DNA sequence; rather, genes may be regulated through DNA methylation, histone modification, chromatin remodeling, and ncRNA interference in response to environmental triggers such as diet, drugs, or stress ( Peng and Zhong, 2015 ; Maldonato et al, 2022 ). Micro-RNAs (miRNAs) and long noncoding RNAs (lncRNAs) are two forms of regulatory ncRNAs that have been shown to alter drug metabolism.…”

Section: Circulating Ncrnasmentioning

confidence: 99%

“…Both miRNAs and lncRNAs modulate the expression of nuclear receptors, drug-metabolizing enzymes, and transporters involved in drug metabolism and disposition in response to stimuli, leading to downstream effects on drug efficacy and toxicity. Figure adapted with permission from Maldonato et al (2022 ) (Taylor & Francis Ltd, http://www.tandfonline.com ).…”

Section: Circulating Ncrnasmentioning

confidence: 99%

“…Given the role of ncRNA in regulating DME expression, it is possible that changes in circulating ncRNA may be reflected in changes to PK parameters that affect drug and metabolite exposure ( Fig. 3 ) ( Ingelman-Sundberg et al, 2013 ; Li et al, 2016 ; Maldonato et al, 2022 ). While many studies have demonstrated associations between miRNA levels and DME expression (see Table 1 ), very few have directly examined the relationship between miRNA and circulating drug or metabolite concentrations in vivo; even fewer studies have been devoted to the influence of lncRNA.…”

Section: Circulating Ncrnasmentioning

confidence: 99%

“…While there is increasing in vitro and ex vivo evidence of the role of ncRNAs in DME expression, more clinical studies are needed to assess the external validity and relevance of circulating ncRNA as a marker for drug PK/PD ( Maldonato et al, 2022 ). For these reasons, more traditional approaches (i.e., use of clinical index enzyme substrates) remain the gold standard for drug metabolism phenotyping.…”

Section: Circulating Ncrnasmentioning

confidence: 99%

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Novel Approaches to Characterize Individual Drug Metabolism and Advance Precision Medicine

et al. 2023

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Interindividual variability in drug metabolism can significantly affect drug concentrations in the body and subsequent drug response. Understanding an individual’s drug metabolism capacity is important for predicting drug exposure and developing precision medicine strategies. The goal of precision medicine is to individualize drug treatment for patients to maximize efficacy and minimize drug toxicity. While advances in pharmacogenomics have improved our understanding of how genetic variations in drug-metabolizing enzymes (DMEs) affect drug response, nongenetic factors are also known to influence drug metabolism phenotypes. This minireview discusses approaches beyond pharmacogenetic testing to phenotype DMEs—particularly the cytochrome P450 enzymes—in clinical settings. Several phenotyping approaches have been proposed: traditional approaches include phenotyping with exogenous probe substrates and the use of endogenous biomarkers; newer approaches include evaluating circulating noncoding RNAs and liquid biopsy-derived markers relevant to DME expression and function. The goals of this minireview are to 1) provide a high-level overview of traditional and novel approaches to phenotype individual drug metabolism capacity, 2) describe how these approaches are being applied or can be applied to pharmacokinetic studies, and 3) discuss perspectives on future opportunities to advance precision medicine in diverse populations. SIGNIFICANCE STATEMENT This minireview provides an overview of recent advances in approaches to characterize individual drug metabolism phenotypes in clinical settings. It highlights the integration of existing pharmacokinetic biomarkers with novel approaches; also discussed are current challenges and existing knowledge gaps. The article concludes with perspectives on the future deployment of a liquid biopsy-informed physiologically based pharmacokinetic strategy for patient characterization and precision dosing.

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Current trends in clinical trials and the development of small molecule epigenetic inhibitors as cancer therapeutics

Zohourian,

Brown

2024

Epigenomics

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Epigenetic mechanisms control and regulate normal chromatin structure and gene expression patterns, with epigenetic dysregulation observed in many different cancer types. Importantly, epigenetic modifications are reversible, offering the potential to silence oncogenes and reactivate tumor suppressors. Small molecule drugs manipulating these epigenetic mechanisms are at the leading edge of new therapeutic options for cancer treatment. The clinical use of histone deacetyltransferases inhibitors (HDACi) demonstrates the effectiveness of targeting epigenetic mechanisms for cancer treatment. Notably, the development of new classes of inhibitors, including lysine acetyltransferase inhibitors (KATi), are the future of epigenetic-based therapeutics. We outline the progress of current classes of small molecule epigenetic drugs for use against cancer (preclinical and clinical) and highlight the potential market growth in epigenetic-based therapeutics.

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Epigenetics in drug disposition & drug therapy: symposium report of the 24^th North American meeting of the International Society for the Study of Xenobiotics (ISSX)

Cited by 3 publications

References 96 publications

Costs of molecular adaptation to the chemical exposome: a focus on xenobiotic metabolism pathways

Costs of molecular adaptation to the chemical exposome: a focus on xenobiotic metabolism pathways

Novel Approaches to Characterize Individual Drug Metabolism and Advance Precision Medicine

Current trends in clinical trials and the development of small molecule epigenetic inhibitors as cancer therapeutics

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Epigenetics in drug disposition & drug therapy: symposium report of the 24th North American meeting of the International Society for the Study of Xenobiotics (ISSX)

Cited by 3 publications

References 96 publications

Costs of molecular adaptation to the chemical exposome: a focus on xenobiotic metabolism pathways

Costs of molecular adaptation to the chemical exposome: a focus on xenobiotic metabolism pathways

Novel Approaches to Characterize Individual Drug Metabolism and Advance Precision Medicine

Current trends in clinical trials and the development of small molecule epigenetic inhibitors as cancer therapeutics

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Product

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Epigenetics in drug disposition & drug therapy: symposium report of the 24^th North American meeting of the International Society for the Study of Xenobiotics (ISSX)