At WCRF International we honour the memory of Professor Fred Kadlubar, who died on December 3rd, 2010, and thank his wife Dr Susan Kadlubar for continuing his research work with us.
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Epidemiological studies have shown that frequent consumption of grilled meats leads to an increased incidence of colorectal and prostate cancer in men, and breast cancer in women. Carcinogenic heterocyclic aromatic amines (HAAs) arise in meats cooked well-done and have been implicated as causal agents of cancer in omonivores. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are two abundant HAAs formed in cooked beef.
Different diets containing vegetables or beverages were examined for their potential to modulate the cytochrome P450 1A2-meidated metabolism of MeIQx and PhIP in volunteers: apiaceous vegetable juice; muscadine grape juice; Fresca; black tea; and non-alcoholic beer, all of which contain phytochemicals that inhibit P450 1A2 activity, were used for study. MeIQx, PhIP, and their metabolites in urine and DNA adducts in saliva, were assayed by liquid chromatography/tandem mass spectrometry.
Our findings show that P450 1A2 significantly contributes to the in vivo metabolism of both HAAs, but with marked differences in substrate specificity. P450 1A2 primarily catalyses the detoxification of MeIQx by oxidation of the 8-methyl group, whereas it catalyses the bioactivation of PhIP by N-oxidation of the exocyclic amine group. However, none of the diets significantly modulated the urinary metabolite profile of either carcinogen. The salivary DNA adducts were at the lower limit of detection, and levels were not influenced by diet.
Our findings indicate that dietary components reported to inhibit P450 1A2 activity and genotoxicity of HAAs in vitro does not translate into chemoprotective effects in vivo, based on the measurement of P450 1A2 metabolic products of HAAs.
Epidemiological studies have shown that frequent consumption of red meat leads to an increased incidence of colorectal, prostate, and breast cancer. An increasing number of studies indicate that this may be due to the presence of compounds known as heterocyclic aromatic amines (HAAs), formed by high temperature cooking methods. Once consumed, metabolism of the HAAs transforms them into substances that damage DNA, leading to cancer. Fortunately, there are dietary constituents found in fruits, vegetables, and beverages that may block these carcinogenic effects.
We hypothesise that frequent consumption of certain diets protects individuals against the carcinogenic effects of HAAs by inhibiting enzymes in the liver that transform HAAs into carcinogenic metabolites that cause DNA damage. Our objective is to assess the efficacy of dietary anti-carcinogens towards HAAs. We will achieve these objectives by measuring HAA-DNA adducts in buccal (cheek) cells and by measuring HAA metabolites in urine from volunteers following consumption of grilled meat on different chemoprotective diets. We expect that dietary components will decrease the production of carcinogenic HAA metabolites by blocking their initial formation and diverting metabolism toward detoxified metabolites. The identification of protective effects will allow us to examine promising, protective foods for extensive studies in large populations.
HAAs are animal carcinogens and undergo metabolism in vitro by enzymes in human liver to produce highly mutagenic species that can damage DNA and lead to cancer. Other dietary components, such as vegetables or fruits may inhibit some liver enyzmes and decrease the genotoxicity of HAAs, based upon studies in vitro. We propose to investigate whether certain fruits and vegetables can exert an inhibitory effect towards HAAs in vivo following consumption of cooked meats, by monitoring urinary metabolites and DNA adducts in saliva, as non-invasive biological fluids.
A controlled feeding study with well-done cooked beef and an intervention diet (apiaceous vegetables (e.g., carrots, celery, parsnips), resveratrol (wine, grape juice), grapefruit juice, tea, or non-alcoholic beer, known to contain inhibitors of cytochrome P450 1A2, the key enzyme involved in bioactivation of HAAs, was given to the subjects. The urinary metabolic profile of two prominent HAAs and their DNA adducts in buccal cells were measured and levels of formation of these biomarkers were examined as a function of the intervention diet.
Our results showed that HAAs are readily absorbed and extensively metabolised by liver, as evidenced by the formation of cytochrome-P450 1A2-derived metabolites excreted in urine. However, dietary intervention components were ineffective at inhibiting the metabolism of both MeIQx and PhIP. Our studies suggest that higher doses of intervention agents and/or a chronic dose regimen, for 1 week or more, may be required to elicit decreases in liver enzyme activities associated with the carcinogenic effects of HAAs.