Skip to 0 minutes and 1 secondThe carcinogenic potential of HCAs requires that they are firstly metabolically activated. HCAs are not carcinogenic in their native state. Bioactivation occurs through a number of steps. Covalent modification of macro molecules, such as DNA, RNA, and protein requires metabolic activation of the HCA. The primary mechanism involves cytochrome P450 mediated n-hydroxylation followed by phase two enzyme metabolism to reactive ester derivatives with N-acetoxy, N-sulfonyloxy, and N-prolyloxy moieties. The esters of N-hydroxy HCAs are metastable and spontaneously rearrange into electrophilic arylnitrenium ion intermediates by heterolytic fission and loss of the ester moiety. The arylnitrenium ion is generally regarded as the ultimate reactive metabolite of HCAs. Arylniternium ion are also formed to a lesser extent from the N-hydroxylamines of certain HCAs, such as IQ and Trp-P-2.
Skip to 1 minute and 23 secondsArylnitrenium ions react with nucleophilic sites on DNA, RNA, or protein. The mutogenicity of the HCAs has also been attributed to the DNA adducts produced from the arylnitrenium ion intermediates. DNA adducts have been characterised for seven HCAs. However, only guanine adducts have been identified. As the N-acetoxy derivatives are not highly reactive with other nucleic acid bases, all HCAs form adducts at the C8 position of guanine. IQ and MeIQx form minor adducts at the N2 atom of guanine. An adduct is a covalent modification of a DNA base, RNA base, or amino acid. Adduction of PhIP occurs at the exocyclic amino group. Adduction of MeIQx also occurs at the exocyclic amino group of the HCA attaching to the C8 atom of guanine.
Skip to 2 minutes and 29 secondsAdduction of other HCAs to C8.
Skip to 2 minutes and 34 secondsLevels of damage depend upon the HCA. This depends on the carcinogenicity of the individual HCA. HCAs fall under the following IARC carcinogen classifications - group 2A and group 2B. Most HCAs consumed by humans are in the IARC classification of class 2B, or possible mutogenetic. Generally, binding of HCAs is associated with corresponding increased binding to proteins, which has given rise to a hypothesis that protein adducted HCAs may be a useful biomarker of DNA adduction. Furthermore, protein adducts are attractive due to their increased abundance compared with DNA. There are some aspects of protein adduction that point toward possible inadequacies as a biomarker. The adduction of carcinogens to blood proteins does not represent genetic damage, per se.
Skip to 3 minutes and 34 secondsAdduction with haemoglobin may not reflect damage in an organ being targeted by cancer as it occurs in red blood cells only. Several studies have addressed the use of HCA adducts as biomarkers. Between 0.01% and 0.04% of dose given was bound to serum protein, and 4 to 10 times more MeIQx adduct was found with albumin than haemoglobin. These studies show that formation of haemoglobin and albumin, adducts of MeIQx, was a linear function of the dose administered. Therefore, these findings raise the possibility that the formation of these serum protein adducts in humans exposed to low doses of HCAs via diet may correlate with the ingested dose, but may be too low to be useful in routine analysis.
Skip to 4 minutes and 26 secondsHCAs are metabolised by human tissue fractions in vitro, and metabolites have been found in urine that suggest these compounds are bioactivated to electrophilic intermediates capable of binding macromolecules. Animal studies have shown that they are linearly related to administered dose over wide dose response ranges down to human dietary exposure levels for MeIQx. In conclusion, HCAs form adducts with macromolecules. Several protein adducts have been identified, though toxicological significance is unknown. The only HCA-DNA adducts identified to date are guanine adducts.
Heterocyclic Amine (HCA) and cancer risk
Diets high in red meat and processed meats are established colorectal cancer (CRC) risk factors. Whilst no conclusive links have yet being established between the dietary intake of heterocyclic amines (HCAs) that accumulate during meat cooking and tumour development, investigations continue in this area.
This video will review the cancer risk associated with HCA exposure and examine the properties contributing to their carcinogenic potential.
You can find out more about HCAs and cancer risk in a factsheet provided by the National Cancer Institute.