Formation of heterocyclic aromatic amines in model systems

doi:10.1016/j.jchromb.2003.09.026

Journal of Chromatography B

Volume 802, Issue 1, 25 March 2004, Pages 3-10

https://doi.org/10.1016/j.jchromb.2003.09.026 Get rights and content

Abstract

Heterocyclic aromatic amines (HAs) are mutagenic and carcinogenic substances that are formed in significant amounts during heating of meat or fish at temperatures of at least 150 °C. To investigate the chemistry lying behind the formation of these harmful substances model systems were established. The first aim was to identify the naturally occurring precursors, namely creatinine, amino acids and carbohydrates. Later these model systems were used to develop strategies for a reduction of the content of the heterocyclic aromatic amines and for the evaluation of the reaction mechanisms that lead to the formation of these substances. All these aspects are discussed in this review.

Introduction

Heterocyclic aromatic amines (HAs) are substances with a high mutagenic and carcinogenic potential [1]. They occur in heated meat and fish. During boiling of meat the HAs are formed at very low concentrations but if the cooking temperature is increased above 150 °C the formation of the HAs increases significantly. These temperatures are reached at the surface when meat or fish is fried, grilled, baked, or roasted. Research on carcinogenicity of heated meat goes back to the year 1939 when the Swedish chemist Widmark found that extracts of fried horse meat induces cancer if they are applied to the skin of mice [2]. Further research on mutagenicity and carcinogenicity was reviewed by Sugimura [3]. The HAs identified and characterized to date are summarized in Table 1. The chemical names that are commonly used are not according to the latest IUPAC rules but give an explanation for the internationally used abbreviations.

In general, the HAs can be divided into two groups namely the polar which are mainly of the imidazoquinoline type (IQ) and imidazoquinoxaline type (IQx) as well as the imidazopyridine type (Fig. 1, Fig. 2) and the non-polar which have a common pyridoindole or dipyridoimidazole moiety (Fig. 3).

The polar HAs are formed from amino acids, carbohydrates and creatinine. Especially creatinine is necessary since from it the imidazo moiety is formed. If it is not present no HAs of the IQ and IQx type are formed. The temperature that is needed for the formation of significant amounts is between 150 and 250 °C. At higher temperatures the non-polar HAs are formed preferably. They are usually assigned as pyrolysis products of the amino acids.

The concentration of the HAs is normally in the low ppb range. Using the Ames test the mutagenicity can be tested using sensitive bacterial test strains. The carcinogenicity was shown in mouse and rat models [3]. The International Agency for Research on Cancer [4] collated the studies on carcinogenicity and classified IQ as probably carcinogenic to humans (Group 2A) and MeIQ as well as MeIQx and PhIP and the apolar HAs AαC, MeAαC, Glu-P-1, Glu-P-2, Trp-P-1, and Trp-P-2 as possibly carcinogenic to humans (Group 2B). Further work on the carcinogenicity of HCA has underlined the mutagenic and carcinogenic potential of these substances.

The formation of the HAs can be studied in chemical model systems [5]. The advantage of the model system is that complex side reactions are reduced and reactions from other constituents of the meat that are not involved in the formation of the HAs are excluded. Additionally, some of the HAs were first identified in the model systems and later found in heated meat.

This review will give a critical overview of the investigative work on formation of these carcinogenic compounds by using model systems.

Section snippets

Identification of the precursors

The first published model systems where mutagenic compounds were identified were pyrolysis reactions of amino acids and proteins. Other food constituents did not form mutagenic substances during pyrolysis [6], [7]. The substances identified were the same as found in the charred parts of roasted or grilled meat and fish [8]. Nucleic acids, starch, or oil did not form mutagenic substances during pyrolysis. Heating of single amino acids also resulted in the formation of mutagenic substances that

Chemistry of HCA formation

At the beginning of last century, Maillard proposed the browning reaction to account for the brown pigments and polymers produced from the reaction of the amino group of an amino acid and the carbonyl group of a sugar [12]. The chemistry underlying the Maillard reaction is very complex. It encompasses not one reaction pathway but a whole network of various reactions. The original comprehensive reactions scheme of Hodge [13] has been improved continuously since that time. At some stages of the

Conclusion

Thus far, several efforts to minimize the mutagen formation in the Maillard-type reaction have been done. The best way to minimize the mutagen formation is by blocking the non-radical pathway of the mutagen formation. Addition of amino acid derivatives reduces the mutagen formation. Jones and Weisburger have demonstrated that tryptophane [45], indole derivatives [46] and proline [47] added to the model system or to beef reduces the mutagen formation by masking the reactive aldehydes. Sugar is

References (49)

T. Sugimura
Mutat. Res.
(1997)
M. Nagao et al.
Cancer Lett.
(1977)
M. Nagao et al.
Cancer Lett.
(1977)
M. Jägerstad et al.
Mutat. Res.
(1991)
E. Borgen et al.
Food Chem.
(2001)
C.I. Wei et al.
Food Chem. Toxicol.
(1981)
M. Jägerstad et al.
Food Chem.
(1983)
C.P. Chiu et al.
Food Chem.
(2000)
H. Lee et al.
Food Chem.
(1992)
A.M. Pearson et al.
Free Radic. Biol. Med.
(1992)

B.L. Milic et al.

Food Chem.

(1993)

M. Johansson et al.

Food Chem.

(1996)

K. Skog et al.

Food Chem. Toxicol.

(1998)

K. Kikugawa et al.

Mutat. Res.

(1999)

A. Oguri et al.

Mutat. Res.

(1998)

K. Wakabayashi et al.

Mutat. Res.

(1997)

K. Skog et al.

Food Chem. Toxicol.

(1998)

K. Skog et al.

Mutat. Res.

(1990)

S. Zöchling et al.

Food Chem.

(2002)

M. Murkovic et al.

Food Chem.

(1999)

R.C. Jones et al.

Mutat. Res.

(1988)

K. Skog et al.

Food. Chem. Toxicol.

(1992)

E. Widmark

Nature

(1939)

T. Sugimura, in: R.H. Adamson, A.A. Gustafsson, N. Ito, M. Nagao, T. Sugimura, K. Wakabyashi, Y. Yamazoe (Eds.),...

Cited by (124)

Exploring the roles of excess amino acids, creatine, creatinine, and glucose in the formation of heterocyclic aromatic amines by UPLC-MS/MS
2024, Food Chemistry
The prevention and control of heterocyclic aromatic amines (HAA) formation to mitigate of potential risks to humans, can be achieved by targeting their precursors. In this study, the detailed roles of individual and excess component (20 common α-amino acids, creatine, creatinine, and glucose) on HAA formation in roasted beef patties were examined using UPLC-MS/MS. The results confirmed the reported classical precursors of HAAs. Some components regulated the competitive production of Norharman and Harman. Glycine (Gly) and glucose favored Norharman formation, while cysteine (Cys) and phenylalanine (Phe) for Harman. Serine (Ser) and threonine (Thr) were identified as potential precursors for IQx-type HAAs. Interestingly, methionine (Met), Gly, Thr, Cys, alanine (Ala), and Ser were revealed as more targeted underlying precursors for 1,6-DMIP and 1,5,6-TMIP, and the formation mechanism was inferred. Furthermore, Pro, Leu, His, Ile, Lys and Asp were considered as great inhibitors for HAAs.
Formation mechanisms, detection methods and mitigation strategies of acrylamide, polycyclic aromatic hydrocarbons and heterocyclic amines in food products
2024, Food Control
Cancer is one of the highest causes of death globally, which is believed to be mainly contributed by unhealthy diet. This review illustrated the formation mechanisms, detection methods and mitigation strategies of three well-known carcinogens, acrylamide, polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs). Acrylamide, which is primarily formed through the Maillard reaction, is a Group 2A carcinogen mostly found in carbohydrate-rich food. PAHs (Group 1, 2A, 2B) and HCAs (Group 2A, 2B) are mainly found in meat and meat products. PAHs are formed from the incomplete combustion of carbonaceous materials through pyrosynthesis and pyrolysis processes. The basic pathway of PAH formation is a primary aromatic ring that undergoes numerous molecular growth reactions such as hydrogen abstraction and acetylene addition (HACA). HCAs are characterized as ‘thermic’ if formed below 300 °C and ‘pyrolytic’ if formed above 300 °C. These two categories of HCAs have different formation mechanisms. The most common detection method for these compounds is GC-MS, LC-MS and HPLC-MS/MS, although HPLC with fluorescence detection has the best performance. The generation of all the three carcinogens is promoted at high temperatures but reduced by cooking at lower temperatures, using different cooking methods such as boiling, or incorporating antioxidants in foods during cooking.
Understanding the heterocyclic aromatic amines: An overview and recent findings
2024, Advances in Food and Nutrition Research
Heterocyclic aromatic amines (HAAs) constitute a group of highly toxic organic compounds strongly associated with the onset of various types of cancer. This paper aims to serve as a valuable resource for food scientists working towards a better understanding of these compounds including formation, minimizing strategies, analysis, and toxicity as well as addressing existing gaps in the literature. Despite extensive research conducted on these compounds since their discovery, several aspects remain inadequately understood, necessitating further investigation. These include their formation pathways, toxic mechanisms, effective mitigation strategies, and specific health effects on humans. Nonetheless, recent research has yielded promising results, contributing significantly to our understanding of HAAs by proposing new potential formation pathways and innovative strategies for their reduction.
Heterocyclic aromatic amines in meat: Formation mechanisms, toxicological implications, occurrence, risk evaluation, and analytical methods
2023, Meat Science
Heterocyclic aromatic amines (HAAs) are detrimental substances can develop during the high-temperature cooking of protein-rich foods, such as meat. They are potent mutagens and carcinogens linked to an increased risk of various cancers. HAAs have complex structures with nitrogen-containing aromatic rings and are formed through chemical reactions between amino acids, creatin(in)e, and sugars during cooking. The formation of HAAs is influenced by various factors, such as food type, cooking temperature, time, cooking method, and technique. HAAs exert their toxicity through mechanisms like DNA adduct formation, oxidative stress, and inflammation. The research on HAAs is important for public health and food safety, leading to risk assessment and management strategies. It has also led to innovative approaches for reducing HAAs formation during cooking and minimizing related health risks. Understanding HAAs' chemistry and formation is crucial for developing effective ways to prevent their occurrence and protect human health. The current review presents an overview about HAAs, their formation pathways, and the factors influencing their formation. Additionally, it reviews their adverse health effects, occurrence, and the analytical methods used for measuring them.
Unveiling heterocyclic aromatic amines (HAAs) in thermally processed meat products: Formation, toxicity, and strategies for reduction – A comprehensive review
2023, Food Chemistry: X
This comprehensive review focuses on heterocyclic aromatic amines (HAAs), a class of chemicals that commonly form during the cooking or processing of protein-rich foods. The International Agency for Research on Cancer (IARC) has categorized certain HAAs as probable human carcinogens, highlighting the significance of studying their formation and control in food safety research. The main objective of this review is to address the knowledge gaps regarding HAAs formation and propose approaches to reduce their potential toxicity during thermal processing. By summarizing the mechanisms involved in HAAs formation and inhibition, the review encompasses both conventional and recent detection methods. Furthermore, it explores the distribution of HAAs in thermally processed meats prepared through various cooking techniques and examines their relative toxicity. Additionally, considering that the Maillard reaction, responsible for HAAs formation, also contributes to the unique flavors and aromas of cooked meat products, this review investigates the potential effects of inhibiting HAAs formation on flavor substances. A thorough understanding of these complex interactions provides a foundation for developing targeted interventions to minimize the formation of HAAs and other harmful compounds during food processing.
The role of flavonoids in mitigating food originated heterocyclic aromatic amines that concerns human wellness
2023, Food Science and Human Wellness
Meat products are an important part in our daily diet, providing valuable nutrients for the human body. However, heating processes cause the meat to become more appetizing with changes in texture, appearance, flavor, and chemical properties by the altering of protein structure and other ingredients. As one kind of cooking-induced contaminants, heterocyclic aromatic amines (HAAs) are widely present in protein aceous food products with strong carcinogenic and mutagenic properties. In order to promote the safety of traditional meat products, this review focused on the formation, metabolism, biological monitoring and inhibitory mechanism of HAA. An overview of the formation pathways, hazards, and control methods of HAAs during food processing in recent years was studied, aiming to provide some valuable information for exploring effective methods to inhibit the production of associated hazards during food processing. Systematic selection of different types of flavonoids to explore their effects on the formation of HAAs in an actual barbecue system can provide theoretical reference for effectively controlling the formation of HAAs and reducing their harm to human health.

View all citing articles on Scopus

View full text

Formation of heterocyclic aromatic amines in model systems

Abstract

Introduction

Section snippets

Identification of the precursors

Chemistry of HCA formation

Conclusion

Mutat. Res.

Cancer Lett.

Cancer Lett.

Mutat. Res.

Food Chem.

Food Chem. Toxicol.

Food Chem.

Food Chem.

Food Chem.

Free Radic. Biol. Med.

Food Chem.

Food Chem.

Food Chem. Toxicol.

Mutat. Res.

Mutat. Res.

Mutat. Res.

Food Chem. Toxicol.

Mutat. Res.

Food Chem.

Food Chem.

Mutat. Res.

Food. Chem. Toxicol.

Nature