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The pitfall of detoxifying enzymes
G Cantelli-Forti1, P Hrelia, M Paolini
1Department of Pharmacology, Genetic and Biochemical Toxicology Units, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy. cantelli@biocfarm.unibo.it
Mutation Research
|July 24, 1998
Summary
Modulating drug-metabolizing enzymes for cancer chemoprevention is complex. While some enzymes detoxify carcinogens, others can activate them, potentially increasing cancer risk and requiring careful reconsideration.
Area of Science:
- Biochemistry
- Toxicology
- Cancer Research
Background:
- Phase-II metabolizing enzymes (e.g., UDP-glucuronosyl transferases, glutathione S-transferases) are crucial for chemical protection against mutagenesis and carcinogenesis.
- Modulating phase-I and phase-II enzymes can influence cancer development, but their dual role (activation/detoxification) presents challenges.
Purpose of the Study:
- To evaluate the complex role of drug-metabolizing enzyme modulators in cancer chemoprevention.
- To investigate the paradoxical use of induced liver preparations in genetic toxicology models.
Main Methods:
- Review of selective inducers of conjugating enzymes and inhibitors of monooxygenases.
- Analysis of the use of exogenous microsomal (S9) fraction from induced rodents (e.g., BHA-treated mice) in genotoxicity assays.
Main Results:
- The dual nature of drug-metabolizing enzymes means that modulation can either reduce or increase cancer risk.
- Induced S9 fractions can enhance the DNA binding and genotoxic response of pre-mutagens, serving as a bioactivating model.
Conclusions:
- The use of enzyme modulators in cancer chemoprevention requires careful consideration due to their potential to increase cancer risk.
- The paradoxical application of induced liver preparations highlights the complexity of xenobiotic metabolism in genetic toxicology.