Genotoxic Assays for Measuring P450 Activation of Chemical Mutagens

This review discusses using yeast as a model organism for studying the biological effects of P450-mediated metabolism of xenobiotics. We discuss the challenges of testing the safety of thousands of chemicals currently introduced into the market place, the limitations of the animal systems, the advantages of model organisms, and the humanization of the yeast cells by expressing human cytochrome P450 (CYP) genes. We discuss strategies in utilizing multiple genetic endpoints in screening chemicals and yeast strains that facilitate phenotyping CYP polymorphisms. In particular, we discuss yeast mutants that facilitate xenobiotic import and retention and particular DNA repair mutants that can facilitate in measuring genotoxic endpoints and elucidating genotoxic mechanisms. New directions in toxicogenetics suggest that particular DNA damaging agents may interact with chromatin and perturb gene silencing, which may also generate genetic instabilities. By introducing human CYP genes into yeast strains, new strategies can be explored for high-throughput testing of xenobiotics and identifying potent DNA damaging agents.

• Publication year

  2019

• Venue

  Genotoxicity and Mutagenicity - Mechanisms and Test Methods

• Publication date

  2019-12-12

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.5772/intechopen.90356
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

• Gut microbial beta-glucuronidase and glycerol/diol dehydratase activity contribute to dietary heterocyclic amine biotransformation

  2019cited by this paper
• DNA damaging agents trigger the expression of the HML silent mating type locus in Saccharomyces cerevisiae.

  2018cited by this paper
• Yeast-based genotoxicity tests for assessing DNA alterations and DNA stress responses: a 40-year overview

  2018cited by this paper
• Carcinogens and DNA damage

  2018cited by this paper
• A Comet Assay for DNA Damage and Repair After Exposure to Carbon-Ion Beams or X-rays in Saccharomyces Cerevisiae

  2018cited by this paper
• CYP1A1 I462V polymorphism is associated with reduced genotoxicity in yeast despite positive association with increased cancer risk.

  2017cited by this paper
• Nucleotide pools dictate the identity and frequency of ribonucleotide incorporation in mitochondrial DNA

  2017cited by this paper
• Thymidylate Depletion Stimulates Homologous Recombination by UNG1 -Dependent and UNG1 Independent Mechanisms in Saccharomyces cerevisiae

  2017cited by this paper
• An in vitro system for measuring genotoxicity mediated by human CYP3A4 in Saccharomyces cerevisiae

  2017cited by this paper
• Construction and comparison of yeast whole-cell biosensors regulated by two RAD54 promoters capable of detecting genotoxic compounds

  2017cited by this paper
• Procarcinogens – Determination and Evaluation by Yeast-Based Biosensor Transformed with Plasmids Incorporating RAD54 Reporter Construct and Cytochrome P450 Genes

  2016cited by this paper
• Recent Structural Insights into Cytochrome P450 Function.

  2016cited by this paper
• Principles of Amnis Imaging Flow Cytometry.

  2016cited by this paper
• Role of Metabolic Enzymes P450 (CYP) on Activating Procarcinogen and their Polymorphisms on the Risk of Cancers.

  2015cited by this paper
• Heritable capture of heterochromatin dynamics in Saccharomyces cerevisiae

  2015cited by this paper
• Systematic humanization of yeast genes reveals conserved functions and genetic modularity

  2015cited by this paper
• Activation of aflatoxin B1 by expression of human CYP1A2 polymorphisms in Saccharomyces cerevisiae.

  2014cited by this paper
• Comparative and Mechanistic Genotoxicity Assessment of Nanomaterials via a Quantitative Toxicogenomics Approach across Multiple Species

  2014cited by this paper
• Optimized proteomic analysis of rat liver microsomes using dual enzyme digestion with 2D-LC-MS/MS.

  2013cited by this paper
• Metabolism and Disposition of Acetaminophen: Recent Advances in Relation to Hepatotoxicity and Diagnosis

  2013cited by this paper
• Optimizations to achieve high-level expression of cytochrome P450 proteins using Escherichia coli expression systems.

  2013cited by this paper
• Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation.

  2013cited by this paper
• Genome instability and aging.

  2013cited by this paper
• Construction and evaluation of two biosensors based on yeast transcriptional response to genotoxic chemicals.

  2013cited by this paper
• Yeast as a humanized model organism for biotransformation-related toxicity.

  2012cited by this paper
• Role of CYP2A5 in the Bioactivation of the Lung Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Mice

  2012cited by this paper
• Contributions of human enzymes in carcinogen metabolism.

  2012cited by this paper
• Benzo[a]pyrene, Aflatoxine B1 and Acetaldehyde Mutational Patterns in TP53 Gene Using a Functional Assay: Relevance to Human Cancer Aetiology

  2012cited by this paper
• Dietary modulation of the biotransformation and genotoxicity of aflatoxin B(1).

  2012cited by this paper
• GENETICS AND BIOGENESIS OF CHLOROPLASTS AND MITOCHONDRIA

  2012cited by this paper
• Metabolism and biomarkers of heterocyclic aromatic amines in molecular epidemiology studies: lessons learned from aromatic amines.

  2011cited by this paper
• Role of biotransformation in drug-induced toxicity: influence of intra- and inter-species differences in drug metabolism.

  2011cited by this paper
• Saccharomyces Genome Database: the genomics resource of budding yeast

  2011cited by this paper
• DNA damage repair and cardiovascular diseases.

  2010cited by this paper
• Construction and validation of a yeast model system for studying in vivo the susceptibility to nucleoside analogues of DNA polymerase gamma allelic variants.

  2010cited by this paper
• Functional characterization of human cytochrome P450 2E1 allelic variants: in vitro metabolism of benzene and toluene by recombinant enzymes expressed in yeast cells

  2010cited by this paper
• Histone deacetylase inhibitors and genomic instability.

  2009cited by this paper
• DNA damage tolerance: when it's OK to make mistakes.

  2009cited by this paper
• Evaluation of the Vitotox and RadarScreen assays for the rapid assessment of genotoxicity in the early research phase of drug development.

  2009cited by this paper
• Enhancement of the recombinagenic and mutagenic activities of bleomycin in yeast by intercalation of acridine compounds into DNA.

  2009cited by this paper
• A sensitive bioassay for the mycotoxin aflatoxin B(1), which also responds to the mycotoxins aflatoxin G(1) and T-2 toxin, using engineered baker's yeast.

  2009cited by this paper
• Stimulation of sister chromatid exchanges and mutation by aflatoxin B1‐DNA adducts in Saccharomyces cerevisiae requires MEC1 (ATR), RAD53, and DUN1

  2008cited by this paper
• Comparison of metabolite profiles generated in Aroclor‐induced rat liver and human liver subcellular fractions: Considerations for in vitro genotoxicity hazard assessment

  2008cited by this paper
• The response of Ty1 test to genotoxins

  2008cited by this paper
• A suite of Gateway® cloning vectors for high‐throughput genetic analysis in Saccharomyces cerevisiae

  2007cited by this paper
• Incident reporting and patient safety

  2007cited by this paper
• Improved cloning and expression of cytochrome P450s and cytochrome P450 reductase in yeast.

  2007cited by this paper
• Genotoxicity of non-covalent interactions: DNA intercalators.

  2007cited by this paper
• The utilization of a Saccharomyces cerevisiae HUG1P-GFP promoter-reporter construct for the selective detection of DNA damage.

  2007cited by this paper
• Endoplasmic Reticulum-Associated Degradation of Cytochrome P450 CYP3A4 in Saccharomyces cerevisiae: Further Characterization of Cellular Participants and Structural Determinants

  2006cited by this paper
• A high-throughput method to measure the sensitivity of yeast cells to genotoxic agents in liquid cultures.

  2006cited by this paper
• The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis

  2006cited by this paper
• An assessment of the utility of the yeast GreenScreen assay in pharmaceutical screening.

  2005cited by this paper
• Cytochrome P450 activation of arylamines and heterocyclic amines.

  2005cited by this paper
• Expression of a Human Cytochrome P450 in Yeast Permits Analysis of Pathways for Response to and Repair of Aflatoxin-Induced DNA Damage

  2005cited by this paper
• Cytochrome P450-mediated metabolism of estrogens and its regulation in human.

  2005cited by this paper
• Enhanced stimulation of chromosomal translocations by radiomimetic DNA damaging agents and camptothecin in Saccharomyces cerevisiae rad9 checkpoint mutants.

  2004cited by this paper
• Transcriptional response of yeast to aflatoxin B1: recombinational repair involving RAD51 and RAD1.

  2004cited by this paper
• Induction of genome instability by DNA damage in Saccharomyces cerevisiae.

  2003cited by this paper
• Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts.

  2003cited by this paper
• Single amino acid mutations, but not common polymorphisms, decrease the activity of CYP1B1 against (-)benzo[a]pyrene-7R-trans-7,8-dihydrodiol.

  2003cited by this paper
• Cadmium is a mutagen that acts by inhibiting mismatch repair

  2003cited by this paper
• Application of the single cell gel electrophoresis on yeast cells.

  2002cited by this paper
• Suppression of spontaneous chromosomal rearrangements by S phase checkpoint functions in Saccharomyces cerevisiae.

  2001cited by this paper
• Liver carcinogen aflatoxin B1 as an inducer of mitotic recombination in a human cell line

  2001cited by this paper
• Analysis of microsatellite mutations in the mitochondrial DNA of Saccharomyces cerevisiae.

  2000cited by this paper
• Damage-induced recombination in the yeast Saccharomyces cerevisiae.

  2000cited by this paper
• Arrest, adaptation, and recovery following a chromosome double-strand break in Saccharomyces cerevisiae.

  2000cited by this paper
• The Ames Salmonella/microsome mutagenicity assay.

  2000cited by this paper
• Initiation of translation in prokaryotes and eukaryotes.

  1999cited by this paper
• Forty years of cytochrome P450.

  1999cited by this paper
• Heterocyclic aromatic amines efficiently induce mitotic recombination in metabolically competent Saccharomyces cerevisiae strains.

  1999cited by this paper
• Inter-individual differences in the metabolism of environmental toxicants: cytochrome P450 1A2 as a prototype.

  1999cited by this paper
• Occupational exposure to genotoxic agents.

  1999cited by this paper
• Expression of Saccharomyces cerevisiae MATa and MATα enhances the HO endonuclease-stimulation of chromosomal rearrangements directed by his3 recombinational substrates

  1999cited by this paper
• Expression of Saccharomyces cerevisiae MATa and MAT alpha enhances the HO endonuclease-stimulation of chromosomal rearrangements directed by his3 recombinational substrates.

  1999cited by this paper
• Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas.

  1999cited by this paper
• Sequence analysis and homology modeling suggest that primary congenital glaucoma on 2p21 results from mutations disrupting either the hinge region or the conserved core structures of cytochrome P4501B1.

  1998cited by this paper
• Yeast as a Model Organism

  1997cited by this paper
• Characterization of Saccharomyces cerevisiae CYP61, Sterol Δ22-Desaturase, and Inhibition by Azole Antifungal Agents*

  1997cited by this paper
• Germ line polymorphisms in cytochrome-P450 1A1 (C4887 CYP1A1) and methylenetetrahydrofolate reductase (MTHFR) genes and endometrial cancer susceptibility.

  1997cited by this paper
• Hydroxyurea induces recombination in dividing but not in G1 or G2 cell cycle arrested yeast cells.

  1996cited by this paper
• Human liver S‐9 metabolic activation: proficiency in cytogenetic assays and comparison with phenobarbital/β‐naphthoflavone or Aroclor 1254 induced ratS‐9

  1996cited by this paper
• 17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1.

  1996cited by this paper
• A C4887A polymorphism in exon 7 of human CYP1A1: population frequency, mutation linkages, and impact on lung cancer susceptibility.

  1996cited by this paper
• Genotoxicity of aflatoxin B1: evidence for a recombination-mediated mechanism in Saccharomyces cerevisiae.

  1996cited by this paper
• Multiple forms of human P450 expressed in Saccharomyces cerevisiae. Systematic characterization and comparison with those of the rat.

  1996cited by this paper
• Yeast expression of animal and plant P450s in optimized redox environments.

  1996cited by this paper
• Cadmium is an inducer of oxidative stress in yeast.

  1996cited by this paper
• Termination-altering mutations in the second-largest subunit of yeast RNA polymerase III

  1995cited by this paper
• Yeast vectors for the controlled expression of heterologous proteins in different genetic backgrounds.

  1995cited by this paper
• Mutation of the gene encoding protein kinase C 1 stimulates mitotic recombination in Saccharomyces cerevisiae

  1994cited by this paper
• Yap1p, a yeast transcriptional activator that mediates multidrug resistance, regulates the metabolic stress response.

  1994cited by this paper
• The sporulation-specific enzymes encoded by the DIT1 and DIT2 genes catalyze a two-step reaction leading to a soluble LL-dityrosine-containing precursor of the yeast spore wall.

  1994cited by this paper
• YAP1 dependent activation of TRX2 is essential for the response of Saccharomyces cerevisiae to oxidative stress by hydroperoxides.

  1994cited by this paper
• DNA-damaging agents stimulate the formation of directed reciprocal translocations in Saccharomyces cerevisiae.

  1994cited by this paper
• Functional co-expression of human oxidoreductase and cytochrome P450 1A1 in Saccharomyces cerevisiae results in increased EROD activity.

  1992cited by this paper
• Optimization of yeast-expressed human liver cytochrome P450 3A4 catalytic activities by coexpressing NADPH-cytochrome P450 reductase and cytochrome b5.

  1992cited by this paper
• Induction of the cytoplasmic 'petite' mutation by chemical and physical agents in Saccharomyces cerevisiae.

  1992cited by this paper
• Targeting, disruption, replacement, and allele rescue: integrative DNA transformation in yeast.

  1991cited by this paper

• No citing papers are available for this paper.