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Isothiocyanates and Xenobiotic Detoxification
Ahmad Faizal Abdull Razis1, Nattaya Konsue2,3, Costas Ioannides3
1Laboratory of Molecular Biomedicine, Institute of Bioscience, Laboratory of Food Safety and Food Integrity, Institute of Tropical Agriculture and Food Security, Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.
Abstract:
The potential of isothiocyanates to antagonize the carcinogenicity of structurally diverse chemicals has been established in animals. A feasible mechanism of action involves protecting DNA by reducing the availability of the genotoxic metabolites of chemical carcinogens by either inhibiting their generation and/or stimulating their detoxification. In vivo as well as in vitro studies conducted in rat/human primary hepatocytes and precision-cut tissue slices have revealed that isothiocyanates can impair cytochrome P450 activity, including the CYP1 family which is the most active in the bioactivation of carcinogens, by virtue of being mechanism-based inactivators. The aromatic phenethyl isothiocyanate is the most effective of those studied, whereas aliphatic isothiocyanates such as sulforaphane and erucin necessitate high doses in order to manifest such effects that may not always be achievable through the diet. In all systems studied, isothiocyanates are strong inducers of detoxification enzyme systems including quinone reductase, glutathione S-transferase, epoxide hydrolase, and UDP-glucuronosyl transferase. Indeed, in smokers phenethyl isothiocyanate intake increases the urinary excretion of inactive mercapturate metabolites of toxic chemicals present in tobacco. Glucosinolates, the precursors of isothiocyanates, have also the potential to upregulate detoxification enzyme systems, but their contribution to the cancer chemoprevention linked to cruciferous vegetable consumption remains to be evaluated.
Insights
Isothiocyanates protect DNA from carcinogens by inhibiting toxic metabolite generation and boosting detoxification. Phenethyl isothiocyanate is most effective, while dietary intake of glucosinolates
Area of Science:
- Biochemistry
- Toxicology
- Cancer Chemoprevention
Background:
- Isothiocyanates are known to counteract chemical carcinogenicity in animal models.
- Their mechanism involves protecting DNA from genotoxic metabolites of carcinogens.
- This protection is achieved by inhibiting metabolite generation and/or enhancing detoxification.
Purpose of the Study:
- To investigate the role of isothiocyanates in modulating carcinogen metabolism and detoxification.
- To compare the efficacy of different isothiocyanates, including aromatic and aliphatic types.
- To explore the impact of isothiocyanates on cytochrome P450 activity and detoxification enzyme systems.
Main Methods:
- In vivo and in vitro studies using rat/human primary hepatocytes and precision-cut tissue slices.
- Assessing the effect of isothiocyanates on cytochrome P450 (CYP1 family) activity as mechanism-based inactivators.
- Evaluating the induction of detoxification enzyme systems such as quinone reductase and glutathione S-transferase.
Main Results:
- Isothiocyanates impair cytochrome P450 activity, particularly CYP1, which is crucial for carcinogen bioactivation.
- Phenethyl isothiocyanate demonstrated higher efficacy compared to aliphatic isothiocyanates like sulforaphane and erucin.
- Isothiocyanates strongly induce detoxification enzymes, leading to increased excretion of detoxified tobacco metabolites in smokers.
Conclusions:
- Isothiocyanates offer a promising strategy for cancer chemoprevention by interfering with carcinogen metabolism.
- Phenethyl isothiocyanate is a potent agent, but high doses of aliphatic isothiocyanates may be needed.
- Further research is needed to evaluate the contribution of dietary glucosinolates to cancer chemoprevention.
