Abstract

Heterocyclic aromatic amines (HAAs) form during the high-temperature cooking of meats, poultry, and fish. Some HAAs also arise during the combustion of tobacco. HAAs are multisite carcinogens in rodents, inducing cancer of the liver, gastrointestinal tract, pancreas, mammary, and prostate glands. HAAs undergo metabolic activation by N-hydroxylation of the exocyclic amine groups to produce the proposed reactive intermediate, the heteroaryl nitrenium ion, which is the critical metabolite implicated in DNA damage and genotoxicity. Humans efficiently convert HAAs to these reactive intermediates, resulting in HAA protein and DNA adduct formation. Some epidemiologic studies have reported an association between frequent consumption of well-done cooked meats and elevated cancer risk of the colorectum, pancreas, and prostate. However, other studies have reported no associations between cooked meat and these cancer sites. A significant limitation in epidemiology studies assessing the role of HAAs and cooked meat in cancer risk is their reliance on food frequency questionnaires (FFQ) to gauge HAA exposure. FFQs are problematic because of limitations in self-reported dietary history accuracy, and estimating HAA intake formed in cooked meats at the parts-per-billion level is challenging. There is a critical need to establish long-lived biomarkers of HAAs for implementation in molecular epidemiology studies designed to assess the role of HAAs in health risk. This review article highlights the mechanisms of HAA formation, mutagenesis and carcinogenesis, the metabolism of several prominent HAAs, and the impact of critical xenobiotic-metabolizing enzymes on biological effects. The analytical approaches that have successfully biomonitored HAAs and their biomarkers for molecular epidemiology studies are presented.

Highlights

  • Professor Takashi Sugimura serendipitously discovered mutagens/carcinogens produced in cooked meat and fish over 40 years ago

  • PhIP hair levels may serve as a biomarker of exposure in epidemiologic studies investigating the association of cooked meat, Heterocyclic aromatic amines (HAAs), and cancer risk

  • We examined the effects of HONH-PhIP (0, 10, up to 1000 nM) on the LNCaP metabolome, [302] employing DHT and tert-butyl hydroperoxide (t-BuOOH) as test compounds for cell proliferation [303] and oxidative stress [304], respectively, since PhIP induces both biological events in the rodent prostate [98]

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Summary

Introduction

Professor Takashi Sugimura serendipitously discovered mutagens/carcinogens produced in cooked meat and fish over 40 years ago. Compared to human liver microsomes, rat and cynomolgus monkey liver microsomes poorly bioactivate IQ, MeIQx, and PhIP to their genotoxic HONH-HAA intermediates because of low CYP1A2 expression but efficiently catalyze HAA ring oxidation, a detoxication pathway, whereas CYPs in human liver microsomes poorly carry out this reaction (Fig. 2) [92, 93, 107, 110,111,112,113, 117].

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