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Metabolic perspectives on in vitro toxicity tests.

F Oesch1, H Glatt, D Utesch

  • 1Institute of Toxicology, University of Mainz, F.R. Germany.

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|January 1, 1988
PubMed
Summary

Chemical toxicity depends on metabolism, which varies significantly. In vitro tests using S9 fractions can be misleading due to the absence of metabolic inactivation, impacting the prediction of in vivo toxicity.

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Area of Science:

  • Toxicology
  • Metabolism
  • In vitro testing

Background:

  • Chemical toxicity is influenced by the parent compound or its metabolites, with metabolism playing a crucial role in controlling toxic species concentration.
  • Metabolism exhibits significant inter-individual variability in humans and animals, necessitating the use of animal models to cover this range.
  • In vitro systems are desirable for mechanistic studies but have historically yielded misleading results due to the lack of adequate metabolic capabilities.

Purpose of the Study:

  • To investigate the role of metabolism in chemical toxicity and the limitations of current in vitro testing methods.
  • To highlight the importance of incorporating accurate metabolic processes in in vitro systems for reliable toxicity predictions.
  • To examine the impact of metabolic activation and inactivation balance on the discrepancies observed between in vitro and in vivo toxicity studies.

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Main Methods:

  • Utilized the S9 fraction, a rat liver supernatant containing microsomal and cytosolic enzymes, to provide metabolic activation capabilities in in vitro systems.
  • Incorporated the NADPH-generating system to optimize mono-oxygenase reactions crucial for metabolic activation of toxic chemicals.
  • Analyzed the balance between metabolic activation and inactivation pathways within both in vitro systems and intact organisms.

Main Results:

  • The S9 fraction enhances metabolic activation but lacks functional metabolic inactivation pathways due to diluted cofactors, leading to an artificial emphasis on activation.
  • Discrepancies between bacterial mutagenicity tests and animal carcinogenicity studies are often attributed to the absence of metabolic inactivation in in vitro systems.
  • The study illustrates the critical role of metabolic information in predicting in vivo adverse effects using chemical derivatives of benz(a)anthracene.

Conclusions:

  • In vitro test systems using S9 fractions can provide misleading results regarding chemical toxicity due to the underrepresentation of metabolic inactivation.
  • Accurate prediction of in vivo toxicity requires in vitro models that properly balance both metabolic activation and inactivation pathways.
  • Future toxicological assessments must integrate comprehensive metabolic data to ensure the predictive value of rapid in vitro screening tests for general toxicity, carcinogenicity, and mutagenicity.