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Development of in vitro models for cellular and molecular studies in toxicology and chemoprevention
K Macé1, E A Offord, C C Harris
1Nestlé Research Center, Lausanne, Switzerland.
Abstract:
Many natural dietary phytochemicals found compounds found in fruits, vegetables, spices and tea have been shown in recent years to be protective against cancer in various animal models. In the light of the potential impact of these compounds on human health it is important to elucidate the mechanisms involved. We therefore developed and characterized relevant in vitro models using immortalized human epithelial cell lines derived from target tissues in carcinogenesis, such as lung, liver and colon. Assays were established, allowing the evaluation of the cytotoxic and genotoxic effects of various procarcinogens, including nitrosamines, mycotoxins and heterocyclic amines on these metabolically-competent human epithelial cell lines. These cellular models appeared to be a useful tool to study the capacity of certain food components to block the initiation stage of carcinogenesis. The ability of carnosol and carnosic acid from rosemary as well as the synthetic dithiolethione, oltipraz, to block the formation of DNA adducts, and their effects on the expression of phase I and phase II enzymes was investigated. We have observed that both rosemary extracts and oltipraz inhibited benzo(a)pyrene- or aflatoxin B1-induced DNA adduct formation by strongly inhibiting CYP450 activities and inducing the expression of glutathione S-transferase. These results in human cell models give some insight into the different mechanisms involved in the chemopreventive action of both natural and synthetic compounds in relation to phase I and phase II enzymes.
Insights
Dietary phytochemicals show cancer-protective effects. Rosemary extracts and oltipraz inhibit DNA adduct formation by modulating CYP450 and glutathione S-transferase (GST) enzymes, revealing chemopreventive mechanisms.
Area of Science:
- Biochemistry
- Toxicology
- Cancer Research
Background:
- Dietary phytochemicals from fruits, vegetables, and tea show promise in cancer prevention across animal models.
- Understanding the mechanisms of action for these compounds is crucial for human health applications.
- In vitro models are essential for studying chemopreventive strategies against carcinogenesis.
Purpose of the Study:
- To develop and characterize human epithelial cell line models for studying carcinogenesis.
- To evaluate the cytotoxic and genotoxic effects of procarcinogens on these models.
- To investigate the chemopreventive mechanisms of rosemary extracts (carnosol, carnosic acid) and oltipraz on DNA adduct formation and enzyme expression.
Main Methods:
- Established immortalized human epithelial cell lines from lung, liver, and colon.
- Developed assays to assess cytotoxic and genotoxic effects of procarcinogens (nitrosamines, mycotoxins, heterocyclic amines).
- Investigated the impact of rosemary extracts and oltipraz on DNA adduct formation and Phase I/II enzyme expression, specifically CYP450 and glutathione S-transferase.
Main Results:
- Rosemary extracts and oltipraz significantly inhibited benzo(a)pyrene- and aflatoxin B1-induced DNA adduct formation.
- These compounds strongly inhibited CYP450 activities, key Phase I enzymes involved in procarcinogen activation.
- Induction of glutathione S-transferase (GST) expression, a Phase II detoxification enzyme, was observed.
Conclusions:
- Human epithelial cell models are effective tools for studying the chemopreventive potential of food components.
- Rosemary extracts and oltipraz exert chemopreventive effects by inhibiting carcinogen activation (CYP450) and enhancing detoxification (GST).
- These findings provide insights into the mechanisms of action for both natural and synthetic chemopreventive agents targeting Phase I and Phase II enzymes.