Metabolism and Biomarkers of Heterocyclic Aromatic Amines in Molecular Epidemiology Studies: Lessons Learned from Aromatic Amines

Abstract

Aromatic amines and heterocyclic aromatic amines (HAAs) are structurally related classes of carcinogens that are formed during the combustion of tobacco or during the high-temperature cooking of meats. Both classes of procarcinogens undergo metabolic activation by N-hydroxylation of the exocyclic amine group, to produce a common proposed intermediate, the arylnitrenium ion, which is the critical metabolite implicated in toxicity and DNA damage. However, the biochemistry and chemical properties of these compounds are distinct and different biomarkers of aromatic amines and HAAs have been developed for human biomonitoring studies. Hemoglobin adducts have been extensively used as biomarkers to monitor occupational and environmental exposures to a number of aromatic amines; however, HAAs do not form hemoglobin adducts at appreciable levels and other biomarkers have been sought. A number of epidemiologic studies that have investigated dietary consumption of well-done meat in relation to various tumor sites reported a positive association between cancer risk and well-done meat consumption, although some studies have shown no associations between well-done meat and cancer risk. A major limiting factor in most epidemiological studies is the uncertainty in quantitative estimates of chronic exposure to HAAs and, thus, the association of HAAs formed in cooked meat and cancer risk has been difficult to establish. There is a critical need to establish long-term biomarkers of HAAs that can be implemented in molecular epidemioIogy studies. In this review article, we highlight and contrast the biochemistry of several prototypical carcinogenic aromatic amines and HAAs to which humans are chronically exposed. The biochemical properties and the impact of polymorphisms of the major xenobiotic-metabolizing enzymes on the biological effects of these chemicals are examined. Lastly, the analytical approaches that have been successfully employed to biomonitor aromatic amines and HAAs, and emerging biomarkers of HAAs that may be implemented in molecular epidemiology studies are discussed.

N-Acetyltransferase 2: ultra-slow acetylators enter the stage

“…Change of subsistence from hunting and gathering to pastoralism and agriculture and the resulting change of ingested xenobiotics are hypothesised as selection factor in favour of slow haplotypes (Sabbagh et al 2011;Luca et al 2008), especially the ultra-slow haplotype NAT2*6A (Patillon et al 2014). Possibly relevant NAT2 substrates in food are, for instance, heterocyclic amines present in well-done meat (Turesky and Le Marchand 2011). Interestingly, European and Northeast Asian populations have a similar frequency of ultra-slow NAT2*6A haplotypes but differ in the slow NAT2*5B, virtually absent in Northeast Asians but frequent in Europeans, and NAT2*7B that is much more frequent in East Asians than in Europeans (Sabbagh et al 2011).…”

Fast Estimation Method of Dietary Exposure to Carcinogenic Compounds in Cooked Meat for Individual Consumer Use

“…The higher is the cooking temperature the higher level of HCAs in meat. HCAs undergo metabolic activation by N-hydroxylation of the exocyclic amine group, to produce a common proposed intermediate, the arylnitrenium ion, which is the critical metabolite implicated in toxicity and DNA damage [19]. HCAs are formed in high-protein content food during heat-treatment in temperatures over 160°C.…”

Acid-labile protein-adducted heterocyclic aromatic amines in human blood are not viable biomarkers of dietary exposure: A systematic study

“…Whilst urine HCA metabolic profiles have been described (Holland et al, 2004), urinary biomarkers are transient, representing only daily HCA exposure and allowing intermittent intake to go undetected (Turesky and Le Marchand, 2011).…”

“…However, the candidacy of labile HCA-protein adducts as biomarkers of HCA exposure has not been conclusively ruled out or, it would appear, subjected to systematic study. PhIP-albumin adducts, in particular, continue to be proposed as potential biomarkers (Turesky and Le Marchand, 2011). The current study aims to conclusively assess the suitability of labile HCA adducts in plasma as biomarkers of dietary HCA exposure by employing high sensitivity mass spectrometry, in vitro HCA-protein control adducts to evaluate efficacy of hydrolysis, and a cohort of human blood samples accompanied by detailed HCA dietary intake information collected in a cross-sectional study of participants consuming their habitual diets.…”