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Metabolic inactivation of mutagens in Drosophila melanogaster

J A Zijlstra1, E W Vogel

  • 1Department of Radiation Genetics and Chemical Mutagenesis, University of Leiden, Sylvius Laboratories, The Netherlands.

Mutation Research
|March 1, 1988
PubMed

Insights

Drug administration route impacts mutagenicity in Drosophila. Oral application led to metabolic deactivation, while injection showed mutagenic effects. Inhibiting cytochrome P-450 restored mutagenicity via feeding.

Area of Science:

  • Pharmacology
  • Toxicology
  • Genetics

Background:

  • Route of drug administration is critical in pharmacology.
  • In Drosophila, a model organism for mutagenicity studies, administration method significantly influences results.
  • Directly acting mutagens' efficacy depends on their delivery and metabolic fate.

Purpose of the Study:

  • To investigate the influence of administration route (feeding vs. injection) on the mutagenicity of directly acting agents in Drosophila.
  • To explore the role of metabolic deactivation in the lack of oral mutagenicity.
  • To assess the impact of cytochrome P-450 inhibition on mutagen delivery and genetic damage.

Main Methods:

  • Determined mutagenicity of Methyl-p-toluenesulphonate (Me-Tos), Ethyl-p-toluenesulphonate (Et-Tos), and nor-nitrogen mustard (NNM) using a sex-linked recessive lethal test in adult Drosophila.
  • Compared mutagenicity after oral feeding versus injection.
  • Administered 1-phenylimidazole (PhI) to inhibit cytochrome P-450 during feeding experiments.
  • Tested formaldehyde (FA) mutagenicity with iproniazid (Ipr) or PhI pretreatment.

Main Results:

  • Me-Tos, Et-Tos, and NNM showed significant mutagenicity upon injection but not when fed to adult flies.
  • Metabolic deactivation, likely in the gut and fat body, explains the absence of oral mutagenicity.
  • Inhibiting cytochrome P-450 with PhI during feeding restored mutagenicity for Me-Tos, Et-Tos, and NNM, indicating a 'first-pass effect'.
  • Formaldehyde mutagenicity was unaffected by PhI or Ipr, suggesting different metabolic pathways.

Conclusions:

  • The route of administration critically affects mutagenicity in Drosophila due to metabolic processes.
  • Cytochrome P-450 plays a key role in the metabolic deactivation of certain mutagens after oral administration.
  • Understanding metabolic pathways is essential for accurate mutagenicity testing and risk assessment.

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