Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Experiment Videos

Strategy for genotoxicity testing--metabolic considerations.

Warren W Ku1, Anita Bigger, Giovanni Brambilla

  • 1Pfizer Global Research and Development, Drug Safety Research and Development, Groton, CT 06340, USA. warren.w.ku@pfizer.com

Mutation Research
|December 5, 2006
PubMed
Summary
This summary is machine-generated.

Related Concept Videos

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Genotoxicity Studies of Indole-3-carbinol and <i>N</i>-Methoxyindole-3-carbinol-The Effect of Sulphotransferases.

Pharmaceuticals (Basel, Switzerland)·2026
Same author

Evaluation of applicability of the repeated-dose liver micronucleus assay in rats initiated at８weeks of age as in vivo genotoxicity assessment for 2,6-dninitrotoluene (2,6-DNT), a compound with reported cytostatic potential.

Mutation research. Genetic toxicology and environmental mutagenesis·2026
Same author

Summary of Major Conclusions From the 8th International Workshop on Genotoxicity Testing (IWGT), Ottawa, Canada.

Environmental and molecular mutagenesis·2026
Same author

Inclusion of a recovery period after pulse treatment in the primary human lymphocyte micronucleus assay covers potential cell cycle delays without loss of sensitivity.

Mutagenesis·2026
Same author

Walk and listen: A multidimensional study on the soundscape of a University District.

PloS one·2026
Same author

Assessment of mutagenic potential of puberulic acid contaminated in red yeast rice (beni-koji) health food supplements.

Mutagenesis·2026

Genotoxicity testing strategies now emphasize metabolic considerations. New approaches include proactive and retroactive strategies for assessing drug metabolite safety and genotoxicity, improving carcinogen detection.

Area of Science:

  • Toxicology and Pharmacology
  • Drug Metabolism and Pharmacokinetics
  • Genotoxicity Testing Strategies

Background:

  • The 2002 International Workshop on Genotoxicity Tests (IWGT) highlighted the need for metabolic considerations in genotoxicity testing strategies.
  • Standard in vitro metabolic activation systems (S9) have deficiencies, leading to missed carcinogen identifications and challenges in drug metabolite safety assessment.

Purpose of the Study:

  • To propose practical strategy recommendations for incorporating metabolic considerations into genotoxicity and carcinogenicity testing.
  • To address shortcomings of current genotoxicity testing, particularly regarding drug metabolites and their activation.

Main Methods:

  • Reviewed current genotoxicity testing deficiencies, including "missed" carcinogens and limitations of the induced S9 system.

Related Experiment Videos

  • Evaluated potential remedies such as alternative S9 sources, external metabolism systems, and engineered test systems.
  • Established consensus principles for strategy development, focusing on human metabolite representation and biotransformation.

    • Main Results:

    • Proposed two strategies: a proactive approach (early metabolism prediction) and a retroactive approach (managing identified major metabolites).
    • Recommended representing human metabolites in testing, using alternative in vitro metabolic activation systems, and selecting appropriate carcinogenicity test species.
    • Defined action triggers for safety assessment based on human exposure and metabolite properties.

    Conclusions:

    • Genotoxicity and carcinogenicity testing must integrate human metabolic data and consider alternative activation systems.
    • Further research is needed to define specific exposure triggers, optimal timing for ADME studies, and the role of in silico/in vitro metabolite analysis.
    • Refined strategies require evaluating current protocols' impact on metabolic activity and exploring novel metabolic activation sources.