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The effects of antioxidants on skin tumor initiation and aryl hydrocarbon hydroxylase
Abstract:
Butylated hydroxytoluene, butylated hydroxyanisole, and vitamins C and E are effective inhibitors of 7,12-dimethylbenz(a)anthracene tumor initiation in a two-stage system of tumorigenesis. These antioxidants did not significantly induce epidermal aryl hydrocarbon [benzo(a)pyrene]hydroxylase, nor did they have any effect when added directly to the in vitro aryl hydrocarbon [benzo(a)pyrene]hydroxylase assay. However, butylated hydroxytolene and butylated hydroxyanisole, when topically to mice, inhibited the in vitro, epidermally mediated, covalent binding of radioactive benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene to DNA. When butylated hydroxytolene and butylated hydroxyanisole were added in vitro, they did not inhibit the epidermally mediated covalent binding of the hydrocarbons to DNA. The inhibition of polycyclic hydrocarbon tumorigenesis by antioxidants may be related to the ability of antioxidants to prevent the in vivo activation of hydrocarbons to carcinogenic epoxides and/or other electrophilic intermediates or may be related to their ability to increase detoxification of the reactive intermediate that requires intact cells to be operational. In any event, the results suggest that the antioxidants have an indirect effect on the epidermal metabolizing system which leads to a decrease in covalent binding to DNA.
Insights
Antioxidants like BHT and BHA inhibit tumor formation by preventing the activation of harmful chemicals into DNA-damaging compounds. These compounds work indirectly by affecting the skin
Area of Science:
- Biochemistry
- Toxicology
- Carcinogenesis
Background:
- Polycyclic aromatic hydrocarbons (PAHs) are environmental carcinogens requiring metabolic activation to exert their effects.
- Tumor initiation is a critical step in carcinogenesis, often involving DNA damage from activated carcinogens.
- Antioxidants are known to modulate cellular processes, but their specific role in carcinogen metabolism requires elucidation.
Purpose of the Study:
- To investigate the inhibitory effects of specific antioxidants on 7,12-dimethylbenz(a)anthracene (DMBA)-induced tumor initiation.
- To determine whether antioxidants interfere with the metabolic activation of PAHs by epidermal enzymes.
- To explore the mechanism by which antioxidants inhibit PAH-induced tumorigenesis, focusing on DNA binding.
Main Methods:
- A two-stage skin tumorigenesis system in mice was employed to assess tumor initiation.
- Epidermal aryl hydrocarbon hydroxylase (AHH) activity was measured in vitro and in vivo.
- The covalent binding of radiolabeled benzo(a)pyrene and DMBA to DNA was quantified in mouse epidermis.
Main Results:
- Butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and vitamins C and E significantly inhibited DMBA-induced tumor initiation.
- Topical application of BHT and BHA inhibited the in vivo epidermal covalent binding of PAHs to DNA.
- These antioxidants did not induce AHH activity nor inhibit PAH-DNA binding when added directly to in vitro assays.
Conclusions:
- Antioxidants BHT and BHA inhibit PAH-induced tumorigenesis through an indirect mechanism.
- The observed inhibition is likely due to the prevention of in vivo activation of PAHs to reactive intermediates or enhanced detoxification.
- Antioxidants modulate the epidermal metabolizing system, reducing the covalent binding of carcinogens to DNA.