Bioactivation by Phase‐<scp>II</scp>‐Enzyme‐Catalyzed Conjugation of Xenobiotics

Grillo, Mark P.

doi:10.1002/9780470921920.edm074

Cited by 5 publications

(6 citation statements)

References 210 publications

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“…The introduction of polar groups by Phase I reactions provides sites that enable conjugation reactions, mediated by Phase II enzymes [ 5 , 7 , 17 , 18 ]. Although Phase II enzymes can directly act on the parent compound [ 19 ], typically Phase I-metabolites are conjugated with charged species, such as glucuronic acid, glutathione, sulfate, amino acids (glycine, taurine, glutamic acid), methyl or acetyl groups. Addition of these large anionic groups, which may detoxify reactive electrophiles (either parent compound or Phase I metabolite), produce Phase II metabolites, with increased hydrophilicity and molecular weight, which in larger part are not able to diffuse across phospholipid membrane barrier (reviewed in Jančová P, Šiller M, 2012) [ 6 , 10 , 11 , 13 , 19 , 20 ].…”

Section: Xenobiotics Disposition and Excretionmentioning

confidence: 99%

“…Although Phase II enzymes can directly act on the parent compound [ 19 ], typically Phase I-metabolites are conjugated with charged species, such as glucuronic acid, glutathione, sulfate, amino acids (glycine, taurine, glutamic acid), methyl or acetyl groups. Addition of these large anionic groups, which may detoxify reactive electrophiles (either parent compound or Phase I metabolite), produce Phase II metabolites, with increased hydrophilicity and molecular weight, which in larger part are not able to diffuse across phospholipid membrane barrier (reviewed in Jančová P, Šiller M, 2012) [ 6 , 10 , 11 , 13 , 19 , 20 ]. Phase III xenobiotic transporters excrete hydrophilic conjugates, with the anionic groups acting as affinity tags for a variety of membrane carriers belonging to two main clusters: ATP binding cassette (ABC), including the multidrug resistance protein (MRP) family, and solute carrier (SLC) transporters (reviewed in Döring B, Petzinger E, 2014) [ 21 , 22 , 23 ].…”

Section: Xenobiotics Disposition and Excretionmentioning

confidence: 99%

“…However, CYP-mediated biotransformation may result in metabolic activation of environmental chemicals to reactive carcinogenic products, a process known as “lethal synthesis” or bioactivation [ 14 , 25 , 82 , 94 , 114 , 119 , 120 ]. While CYPs may catalyze the activation of procarcinogens to electrophilic ultimate carcinogens, the Phase II enzymes in general detoxify electrophilic intermediates into non-toxic substrates, with few exceptions of non-canonical bioactivation through conjugation reactions [ 19 ]. The potentially toxic reactive metabolites that “escape” from Phase II metabolism are able to covalently interact with nucleophilic structures such as those of nucleic acids, proteins, or lipids, causing cell damage and potentially triggering carcinogenesis, teratogenicity, and/or adverse drug reactions (ADRs) [ 1 , 3 , 20 , 58 , 103 , 104 , 105 , 114 , 120 ] ( Figure 1 ).…”

Section: The Central Role Of Cytochrome P450s As Xenobiotic-metabolizing Enzymesmentioning

confidence: 99%

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The Central Role of Cytochrome P450 in Xenobiotic Metabolism—A Brief Review on a Fascinating Enzyme Family

Esteves

Rueff

Kranendonk

2021

JoX

242

146

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Human Cytochrome P450 (CYP) enzymes constitute a superfamily of membrane-bound hemoproteins that are responsible for the metabolism of a wide variety of clinically, physiologically, and toxicologically important compounds. These heme-thiolate monooxygenases play a pivotal role in the detoxification of xenobiotics, participating in the metabolism of many structurally diverge compounds. This short-review is intended to provide a summary on the major roles of CYPs in Phase I xenobiotic metabolism. The manuscript is focused on eight main topics that include the most relevant aspects of past and current CYP research. Initially, (I) a general overview of the main aspects of absorption, distribution, metabolism, and excretion (ADME) of xenobiotics are presented. This is followed by (II) a background overview on major achievements in the past of the CYP research field. (III) Classification and nomenclature of CYPs is briefly reviewed, followed by (IV) a summary description on CYP’s location and function in mammals. Subsequently, (V) the physiological relevance of CYP as the cornerstone of Phase I xenobiotic metabolism is highlighted, followed by (VI) reviewing both genetic determinants and (VI) nongenetic factors in CYP function and activity. The last topic of the review (VIII) is focused on the current challenges of the CYP research field.

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Section: Xenobiotics Disposition and Excretionmentioning

confidence: 99%

Section: Xenobiotics Disposition and Excretionmentioning

confidence: 99%

Section: The Central Role Of Cytochrome P450s As Xenobiotic-metabolizing Enzymesmentioning

confidence: 99%

See 1 more Smart Citation

The Central Role of Cytochrome P450 in Xenobiotic Metabolism—A Brief Review on a Fascinating Enzyme Family

Esteves

Rueff

Kranendonk

2021

JoX

242

146

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“…P450s catalyze a variety of reactions, including aliphatic and aromatic hydroxylation, N - or O -dealkylation, aliphatic desaturation, hetero atom oxidation, and epoxidation reactions [ 2 ]. The resulting metabolites can contain functional groups such as –OH, –NH 2 , and –SH which can undergo conjugation reactions by phase II enzymes, including UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), N -acetyltransferases (NATs), glutathione S -transferases (GSTs), and methyltransferases [ 3 ].…”

Section: Metabolism Bioactivation and Dna Adducts As Biomarkers mentioning

confidence: 99%

Formalin-Fixed Paraffin-Embedded Tissues—An Untapped Biospecimen for Biomonitoring DNA Adducts by Mass Spectrometry

Yun

Guo

Turesky

2018

Toxics

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The measurement of DNA adducts provides important information about human exposure to genotoxic chemicals and can be employed to elucidate mechanisms of DNA damage and repair. DNA adducts can serve as biomarkers for interspecies comparisons of the biologically effective dose of procarcinogens and permit extrapolation of genotoxicity data from animal studies for human risk assessment. One major challenge in DNA adduct biomarker research is the paucity of fresh frozen biopsy samples available for study. However, archived formalin-fixed paraffin-embedded (FFPE) tissues with clinical diagnosis of disease are often available. We have established robust methods to recover DNA free of crosslinks from FFPE tissues under mild conditions which permit quantitative measurements of DNA adducts by liquid chromatography-mass spectrometry. The technology is versatile and can be employed to screen for DNA adducts formed with a wide range of environmental and dietary carcinogens, some of which were retrieved from section-cuts of FFPE blocks stored at ambient temperature for up to nine years. The ability to retrospectively analyze FFPE tissues for DNA adducts for which there is clinical diagnosis of disease opens a previously untapped source of biospecimens for molecular epidemiology studies that seek to assess the causal role of environmental chemicals in cancer etiology.

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“…The data provided highlight specific non-P450 enzymes which require greater characterization. Greater knowledge of the involvement and importance of non-P450 enzymes can result in consideration of other factors for these enzymes, such as species differences, hepatic versus extrahepatic expression and metabolism, enzyme polymorphisms (Brian et al, 2016), likely DDIs, non-P450-mediated bioactivation (Grillo and Lyubimov, 2011;Hutzler and Cerny, 2012), as well as the development of in vitro assays to improve extrapolation to predict and understand in vivo CL for these non-P450 enzymes. Improving our understanding of these metabolic enzymes and biotransformations should result in fewer surprises being encountered during the drug discovery and development process, leading to safer drugs in the future.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Non-Cytochrome P450-Mediated Metabolism in Food and Drug Administration-Approved Oral and Intravenous Drugs: 2006-2015

Cerny

2016

Drug Metabolism and Disposition

124

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In recent years, claims of increased involvement of non-cytochrome P450 (non-P450) enzymes in the metabolism of drugs have appeared in the literature. However, no temporal summaries of the contribution of non-P450 enzymes to the metabolism of drugs have been published. Using data from human radiolabeled absorption, distribution, metabolism, and excretion studies available for a set of 125 orally or intravenously administered small-molecule drugs approved by the United States Food and Drug Administration from 2006 to 2015, the contributions of P450 and non-P450 enzymes to the formation of major metabolites ( ‡10% of dose) were assessed and tabulated. Over this time frame, the involvement of P450 versus non-P450 enzymes in the formation of major metabolites is compared, and the individual non-P450 enzymes responsible are described. This analysis indicates that non-P450 enzymes contribute significantly to the metabolism of the 125 drugs analyzed. Approximately 30% of the metabolism of these drugs is carried out by non-P450 enzymes, with the predominant non-P450 enzymes identified being glucuronosyltransferases (11.7%), hydrolases (10.8%), carbonyl reductases (2.4%), and aldehyde oxidase (1.1%). Although significant, the relative contribution of non-P450 enzymes to drug metabolism does not appear to have increased dramatically over the last 10 years. As the current evaluation involves drugs which emerged from the discovery phase >10 years ago, this evaluation may not reflect the current or evolving situation in some research organizations; therefore, additional monitoring and assessment of the involvement of non-P450 enzymes in the metabolism of drugs will be conducted in the future.

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Bioactivation by Phase‐II‐Enzyme‐Catalyzed Conjugation of Xenobiotics

Cited by 5 publications

References 210 publications

The Central Role of Cytochrome P450 in Xenobiotic Metabolism—A Brief Review on a Fascinating Enzyme Family

The Central Role of Cytochrome P450 in Xenobiotic Metabolism—A Brief Review on a Fascinating Enzyme Family

Formalin-Fixed Paraffin-Embedded Tissues—An Untapped Biospecimen for Biomonitoring DNA Adducts by Mass Spectrometry

Prevalence of Non-Cytochrome P450-Mediated Metabolism in Food and Drug Administration-Approved Oral and Intravenous Drugs: 2006-2015

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