Preventive Potential and Mechanism of Dietary Polyphenols on the Formation of Heterocyclic Aromatic Amines

Received: 1 June 2020 Revised: 19 June 2020 Accepted: 19 June 2020

DOI: 10.1002/fft2.30

REVIEW ARTICLE

Preventive potential and mechanism of dietary polyphenols on the formation of heterocyclic aromatic amines

Hui Cao1 Bing-Huei Chen2 Baskaran Stephen Inbaraj2 Lei Chen1 Gerardo Alvarez-Rivera3 Alejandro Cifuentes3 Nana Zhang4 Deng-Jye Yang5 Jesus Simal-Gandara6 Mingfu Wang4 Jianbo Xiao7

1 College of Food Science, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China

2 Department of Food Science, Fu Jen Catholic University, New Taipei City, Taiwan

3 Laboratory of Foodomics, Institute of Food Science Research, CIAL, CSIC, Madrid, Spain

4 School of Biological Sciences, The University of Hong Kong, Hong Kong 5 Institute of Food Safety and Health Risk Assessment, National Yang-Ming University, Taipei, Taiwan

6 Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo-Ourense Campus, Ourense, Spain

7 Institute of Food Safety and Nutrition, Jinan University, Guangzhou, China

Correspondence Jianbo Xiao, Institute of Food Safety and Nutri- Abstract tion, Jinan University, Guangzhou 510632, China. Thermal processing is the most important and popular domestic cooking method. More Email: [email protected] than 30 heterocyclic aromatic amines have been identified in cooked meat using var- Mingfu Wang, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, ious methods. This review highlights preventive potential and mechanism of dietary Hong Kong. polyphenols on the formation of heterocyclic amines. Tea, coffee, fruits, vegetable, and Email: [email protected] Jesus Simal-Gandara, Nutrition and Bromatol- spice extracts rich in polyphenols exerted significant inhibition against the formation of ogy Group, Department of Analytical Chem- heterocyclic aromatic amines. Some polyphenols, such as naringenin and epigallocate- istry and Food Science, Faculty of Food Science and Technology, University of Vigo-Ourense chin 3-O-gallate, can actively participate into food chemistry reaction to trap Strecker Campus, E-32004 Ourense, Spain. aldehyde and lower the formation of heterocyclic aromatic amines. In addition, some Email: [email protected] polyphenols can lower the mutagenicity of heterocyclic aromatic amines. More specif- ically, polyphenols possessing two hydroxyl groups at the meta position of aromatic ring are the most efficient one, but the presence of carboxylic or alkyl groups as sub- stituents in the aromatic ring slightly reduced the inhibitory effect.

KEYWORDS heterocyclic aromatic amines, inhibition, polyphenols, structure–activity relationship

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2020 The Authors. Food Frontiers published by John Wiley & Sons Australia, Ltd and Nanchang University, Northwest University, Jiangsu University, Zhejiang Univer- sity, Fujian Agriculture and Forestry University

134 wileyonlinelibrary.com/journal/fft2 Food Frontiers. 2020;1:134–151. CAO ET AL. 135

1 HAZARDS LINKED TO FOOD THERMAL 2 FORMATION OF HETEROCYCLIC AROMATIC PROCESSING AMINES

Thermal processing is the most important and popular domestic The formation pathways of HAAs are usually investigated in chemi- cooking method. It has many benefits such as improving nutri- cal model systems to reduce side reactions and exclude the effects tional quality, enhancing bioavailability of nutrients, prolonging of other components. According to the structure differences and for- shelf life, obtaining better flavor, producing bioactive compounds, mation pathway, HAAs can be divided into aminoimidazoazarenes and improving food safety (Zhao et al., 2019). On the other hand, (AIAs) and pyrolytic HAAs. AIAs include quinoxalines (IQx, MeIQx, it can also bring some undesired consequences including losing DiMeIQx, etc.), quinolines (IQ, MeIQ, etc.), and pyridines (PhIP, DMIP, nutrients, forming toxic compounds, causing unpleasant flavor, etc.), while pyrolytic HAAs mainly include α-carbolines (AαC, MeAαC), and so on (Friedman, 2015; Mogol & Gokmen, 2016). In particular, β-carbolines (harman and norharman), γ-carbolines (Trp-P-1, Trp-P-2), the mutagenic compounds, such as acrylamide, acrolein, polycyclic δ-carbolines (Glu-P-1, Glu-P-2), and phenyl pyridine (Phe-P-1) (Bus- aromatic hydrocarbons (PAHs), and heterocyclic aromatic amines quets, Bordas, Toribio, Puignou, & Galceran, 2004; Kizil, Oz, & Besler, (HAAs), are formed during the thermal processing of various foods 2011). (Fasano, Yebra-Pimentel, Martinez-Carballo, & Simal-Gandara, 2016; Garcia-Falcon & Simal-Gandara, 2005; Rey-Salgueiro, Garcia-Falcon, Martinez-Carballo, Gonzalez- Barreiro & Simal-Gandara, 2009;Rey- 2.1 Formation of quinoxalines and quinolines Salgueiro, Garcia-Falcon, Martinez-Carballo, & Simal-Gandara, 2008, HAAs Rey-Salgueiro, Garcia-Falcon, Martinez-Carballo, & Simal-Gandara, 2009; Singh, Agarwal, & Simal-Gandara, 2020; Viegas, Yebra-Pimentel, AIAs are mainly formed by dehydration and cyclization of amino acids Martinez-Carballo, Simal-Gandara, & Ferreira, 2014; Yebra-Pimentel, and sugars at temperatures between 100 and 300◦C to form pyrrole Fernandez-Gonzalez, Martinez-Carballo, & Simal-Gandara, 2012; or pyrazine, and then condensation with creatinine and aldehydes Yebra-Pimentel, Martinez-Carballo, Regueiro, & Simal-Gandara, produced by Strecker degradation (Kizil et al., 2011). Specifically, as for 2013). More than 30 HAAs compounds (Figure 1) have been identified the formation of IQ-type HAAs, an early study has proposed a possible in cooked meat using various methods. HAAs compounds can be pathway, as shown in Figure 2, creatinine forms the aminoimidazole classified into thermic and pyrolytic types according to their formation part through cyclization and dehydration, while the remaining part of temperature. The thermic HAAs with a chemical structure of aminoim- IQ-type HAAs is derived from Strecker degradation products such as idazoazarene are commonly formed under relative low temperatures pyridine and pyrazine. The two parts are then linked by butyraldehyde (∼200◦C), and the pyrolytic HAAs (mainly amino-carbolines) are pro- condensation via Strecker reaction products such as aldehyde or duced by pyrolysis of amino acids and proteins at higher temperatures Schiff base (Jägerstad, Reuterswärd, Olsson, et al. 1983; Jägerstad, (250◦C) (Zamora & Hidalgo, 2020). Reuterswärd, Öste et al., 1983). This pathway was further validated The levels of specific HAAs compounds are different with the meat and refined by Nyhammar (1986). However, Jones and others believed type, cooking method, temperature, time, and doneness level. Other that in the case of the same precursors, creatinine might condense factors are determined by the various food substrates, including pH, with aldehyde first before reacting with pyridine or pyrazine to form IQ contents of precursors, presence of certain divalent ions, types of or IQx compounds (Jones & Weisburger, 1988). Subsequently, Pearson amino acids, and content of substances with enhancing or inhibit- and others proposed two free radical pathways (Figure 2), which ing effects (Gibis, 2016). The imidazo moiety is originated from the suggest that alkylpyridine free radicals react with creatinine to form creatinine; moreover, if the creatinine is absent, no imidazoquinoline IQ and MeIQ, while MeIQx and 4,8-DiMeIQx are formed between and imidazoquinoxaline are formed. However, the generation of the dialkylpyrazine free radicals and creatinine. Specifically, the former pyrolytic HAAs does not require the existence of creatinine. PhIP involves bimolecular ring formation from the enaminol form of the appears to be formed more easily in chicken than in beef, pork or glycoaldehyde alkylamine and followed by the oxidative formation of fish, while the amount of MeIQx in cooked chicken is usually lower free radicals. The later involves N,N1-diakylpyrasinium ions formation than in cooked beef and pork. For a given cooking condition, the from glyoxal monoalkylamine and then form the free radicals through amount of PhIP, MeIQx, and AαC in ordinary muscle was higher than reduction (Pearson, Chen, Gray, & Aust, 1992). the dark muscle. It also can be observed that less browning inten- sity on the meat surface of the dark muscle than the ordinary mus- cle, enhances the formation of HAAs. Moreover, the ordinary muscle 2.2 Formation of pyridines HAAs contains higher free amino acids, moisture, and nitrogen compounds than dark muscle, which also facilitate the formation of carcinogenic Phenylalanine and creatinine have been confirmed to be the precursors HAAs. of PhIP formation via 13C labeling method, while glucose was found not 136 CAO ET AL.

FIGURE 1 Chemical structures of heterocyclic amines formed during food processing CAO ET AL. 137

FIGURE 2 Proposed pathways for the formation of quinoxalines (IQx, MeIQx, DiMeIQx, etc.) and quinolines (IQ, MeIQ, etc.) HAAs a necessary precursor under dry heating conditions and excessive glu- nitrogen, and benzene ring of phenylalanine, as well as the amino nitro- cose may inhibit PhIP formation to a certain extent (Felton & Knize, gen and the nitrogen atom in the ring of creatine all participate in the 1990; Skog, Johansson, & Jägerstad, 1998). The formation of PhIP in formation of PhIP. Therefore, it is speculated that the pyridine part of phenylalanine–creatinine model system mainly includes the following PhIP is from phenylalanine, while the imidazole part is from creatinine steps: First, phenylalanine undergoes the Strecker degradation process (Felton, Knize, Hatch, Tanga, & Colvin, 1999). to form phenylacetaldehyde, which then reacts with creatinine via aldol condensation (Figure 3). The dehydrated aldol condensation product finally forms PhIP with the aid of Schiff base (Murkovic, Weber, Geis- 2.3 Formation of amino-carbolines zler, Fröhlich, & Pfannhauser, 1999).This pathway was proven by Zöch- ling and others who identified the condensation products in both chem- Amino-carbolines are mainly formed by pyrolysis of amino acids or ical model systems and heated meats (Zöchling & Murkovic, 2002). proteins at temperatures above 300◦C (Kizil et al., 2011). Currently, Further mechanistic results found the side chain carbon atoms, amino researchers have proposed a clear pathway regarding the formation of 138 CAO ET AL.

FIGURE 3 Proposed pathways for the formation of pyridines (PhIP, DMIP, etc.) HAAs norharman in β-carbolines. As shown in Figure 4, briefly, the Amadori (Ahmad Kamal, Selamat, & Sanny, 2018; Yan et al., 2017), disper- rearrangement product of tryptophan (an important precursor for sive liquid-liquid microextraction (DLLME) (Aeenehvand et al., 2016; norharman formation) undergoes the dehydration reaction in the form Canales, Guiñez, Bazán, Reta, & Cerutti, 2017), solid-phase microex- of furan, followed by β-elimination with the help of epoxy lone pair traction (SPME) (Cagliero, Ho, Zhang, Bicchi, & Anderson, 2016; Zhang, electrons to form conjugated oxonium ion (2), which can stabilize itself Cheng, Li, & Xiao, 2015), and QuEChERS (Quick, Easy, Cheap, Effective, through dehydration and formation of an extended conjugated sys- Rugged, Safe) (Chang, Zhang, Wang, & Chen, 2019; Xian et al., 2019) tem, or through the splitting of C-C bond to produce a furan deriva- have been employed for extraction and clean-up of HAAs, significantly tive (3) and an imidium cation. Finally, the intermediate undergoes a improving the selectivity and sensitivity in the analysis of HAAs (Dong, nucleophilic substitution to form β-carboline (Finot, 1990). In addi- Xian, Li, Bai, & Zeng, 2020). tion, tetrahydro-β-carboline (THβC), 1,2,3,4-tetrahydro-β-carboline-3- Over the last decades, numerous instrumental methods of analysis carboxylic acid (THCA), and 1-methyl-1,2,3,4-tetrahydro-β-carboline- have been reported for the identification and quantitation of HAAs 3-carboxylic acid (MTCA) are also considered to be the intermedi- in various foodstuffs, mainly using chromatographic techniques. ates for the formation of norharman and harman, namely, tryptophan Liquid chromatography (LC) is widely used in HAAs analysis in com- reacts with acetaldehyde or α-ketoacidtoformTHβC through Strecker bination with ultraviolet (Lu, Kuhnle, & Cheng, 2017), fluorescence degradation reaction, and then undergoes a series of oxidation and (Martín-Calero, Ayala, González, & Afonso, 2009), photodiode array decarboxylation to form β-carboline (Herraiz, 2000; Totsuka et al., (Vichapong, Burakham, & Srijaranai, 2017), and amperometric detec- 1999). tors (Bueno, Marín, Contento, & Ríos, 2016). The use of cheaper spectroscopic detectors in most of these methods provides several advantages when sample preparation and chromatographic separation 3 METHODS TO CHARACTERIZE are satisfactory. However, the low sensitivity and selectivity of these HETEROCYCLIC AROMATIC AMINES methods might not be sufficient to identify HAAs in the presence of interfering impurities. Owing to the presence of HAAs at a trace level (usually μgkg−1 For that reason, LC and gas chromatography (GC) methods are or ppb) in highly complex food matrices, effective sample prepara- mostly used coupled to mass spectrometry (MS) detectors since their tion procedures are required to improve accuracy and detectability hyphenation gives rise to powerful techniques to determine HAAs in before the instrumental analysis. In recent years, convenient and easy- different samples (Barzegar, Kamankesh, & Mohammadi, 2019; Chen, to-use extraction approaches based on solid-phase extraction (SPE) Jia, Zhu, Mao, & Zhang, 2020; Dong, Xian, Li, Bai et al., 2020). LC-MS CAO ET AL. 139

FIGURE 4 Proposed pathway for the formation of norharman (Finot, 1990)

and LC-tandem mass spectrometry (MS/MS) methods are the most butyldimethylsilyl (TBDMS), have been proposed for GC-MS deter- frequently used analytical approaches for the unambiguous detec- mination of HAAs (Casal, Mendes, Fernandes, Oliveira, & Ferreira, tion of HAAs, which combine the robustness and effective separa- 2004; Dong, Xian, Li, Bai et al., 2020; Warzecha et al., 2004). The tion of HPLC with the high sensitivity and selective of MS instru- results from a comparative study between different derivatization ments. Thus, several HPLC-ESI-MS/MS methods have been recently procedures based on the formation of Schiff bases using N,N- reported for the analysis of several HAAs in commercial meat prod- dimethylformamide dialkylacetals reagents before GC-MS revealed ucts (Chang et al., 2019; Hsiao, Chen, & Kao, 2017; Jian, Yeh, Wang, that N,N-dimethylformamide di-tert-butylacetal (DMF-DtBA) pro- Chen, & Chen, 2019) as well as roasted coffee (Xian et al., 2019)with vided the highest sensitivity (Barceló-Barrachina, Santos, Puignou, & good recoveries and sensitivity. LC methods couplet to high-resolution Galceran, 2005). Silylation-GC-MS was also an effective methodology mass spectrometry (HRMS) such as quadrupole time-of-flight mass for the analysis of HAAs in cigarette smoke condensate (Liu, Taylor, spectrometry (q-TOF-MS) (Barceló-Barrachina, Moyano, & Galceran, Borgerding, Coleman, & Bombick, 2013). Despite several advantages 2004), ion-trap time-of-flight-MS (LC-IT-TOF-MS) (Ouyang, Li, Tang, of GC-MS methods (e.g., simplicity, high sensitivity, and separation Jin, & Li, 2015), and quadrupole-Orbitrap HRMS (Q-Orbitrap HRMS) efficiency), derivatization is a time-consuming procedure, and only (Dong, Xian, Li, Wu et al., 2020) allow obtaining accurate HRMS data some nonpolar HAAs can be properly derivatized. Furthermore, the for quantification operating in full MS mode, and product ion spec- high temperature in the injection port might led to HAAs generation tra for identification operating in data-dependent or independent scan from coextracted HAAs precursors, leading to false results (Hsiao et al., mode. 2017). Although GC-MS methods are less frequently used to determine Other analytical methodologies reported for HAAs analysis include HAAs, they are suitable strategies for the analysis of less-polar capillary zone electrophoresis (CZE) with ultraviolet-diode array or nonpolar HAAs, which very frequently require a derivatiza- detector (Fei, Li, Yu, & Chen, 2007), capillary electrophoresis (CE) with tion procedure to increase their volatility. Several derivatization fluorescence detection (De Andrés, Zougagh, Castañeda, & Ríos, 2010), methods, including alkylation of the primary amino group with and ultra-fast liquid chromatography with ultraviolet visible detector 3,5-bistrifluoromethylbenzyl bromide (3,5-bisTFMBB), acylation employed to detect HAAs in cooked frozen meat products (Oz & Kızıl, with pentafluoropropionic anhydride, and silylation with tert- 2013). 140 CAO ET AL.

4 TOXICOLOGY OF HETEROCYCLIC AROMATIC and MeIQx. β-Carbolines derivatives such as harman and norharman AMINES did not show mutagenic activity in the Ames test; however, both com- pounds could behave as comutagens, strengthening the mutagenic The generation of HAAs during thermal processing of protein–rich activity of other HAAs (Pfau & Skog, 2004). foods, for example, meat, poses a health risk to the consumers associ- Carcinogenicity and mutagenicity of HAAs has also been proven in ated to the dietary intake of these toxicants. In particular, HAAs may experimental animals (Chen et al., 2020; Kohno et al., 2007). These have detrimental effects on the human body, eventually acting as muta- toxic components induced tumors in different organs of mice and rats, genic and carcinogenic substances (Barzegar et al., 2019). HAAs are such as intestine and liver (Ohgaki et al., 1987). Monkeys were also reported to be tenfold more carcinogenic than other toxic substances shown to develop liver cancer when dosed with IQ, demostrating that such as as nitrosamines, aflatoxins B1, and benzo[α]pyrene (Püssa, some HAAs are carcinogens not only to rodents, but also to other 2013). Several HAAs, including 2-amino-3,4-dimethylimidazo [4,5-f] higher mammals (Adeyeye, 2018). quinoline (MeIQ) and 2-amino-3,8-dimethylimidazo [4,5-f] quinoxaline At metabolic level, HAAs could increase the risk of chronic patholo- (MeIQx), 2-Amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP), gies such as cardiovascular disease and obesity, besides cancer, by 2-Amino-9H-pyrido[2,3-b]indol (AαC), and 2-Amino-3-methyl-9H- triggering oxidative stress processes (Carvalho et al., 2015). Like pyrido[2,3-b]indol (MeAαC), were highlighted as possible carcinogens most carcinogens, HAAs exert mutagenic activity after activation by to humans (group 2B) by the International Agency for Research on metabolic enzymes. HAAs are absorbed in the small intestine and then Cancer (IARC) and World Health Organization (WHO), whereas transported to the liver where they undergo activation (Lynch, Mur- 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was classified as a ray, Gooderham, & Boobis, 1995). Different HAAs are metabolized probable carcinogen in group 2A (Adeyeye, 2018). in humans by several enzymes, including cytochrome P450s, perox- The results from various epidemiological surveys revealed that idases, N-acetyltransferases, sulfotransferases, uridine diphosphate- HAAs are one of the leading factors in breast, colon, pancreatic, glucuronosyltransferases, and glutathione S-transferases. Metabolic and other cancers (Barzegar et al., 2019; Namiranian, Moradi-Lakeh, activation of HAAs starts with N-oxidation by cytochrome enzymes Razavi-Ratki, Doayie, & Nojomi, 2014; Oba et al., 2006; Paluszkiewicz, and further acetylation. The genereated N-acetoxyamine is a reactive Smolińska, Dębińska, & Turski, 2012). In this line, high intake of MeIQ product of the previous reaction that can lead to DNA damage and and total HAAs was associated with an increased risk of colorec- eventual mutations (Barzegar et al., 2019). Their primary metabolites tal adenoma in women but not in men (Budhathoki et al., 2015). A are further conjugated with DNA or ultimately excreted in urine and recent meta-analysis summarized that dietary HAAs intake, including feces. The 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in hair as PhIP and DiMeIQx, was positively linked with the risk of colon cancer. well as DNA, hemoglobin, and serum albumin adducts have been con- Interestingly, several large-scale cohort studies that showed associa- sidered as biomarkers for exposure assessment (Chen et al., 2020). tion between the intakes of HAAs (e.g., PhIP and MeIQx) and higher cancer risk revealed that red meat consumption largely contributed to the above positive associations (Gibis, 2016). Athough the causal- 5 INHIBITION OF EXTRACTS RICH IN ity between meat consumption and cancer risk is difficult to clarify, POLYPHENOLS ON HAAS FORMATION dietary intake information obtained from questionnaires and epidemi- ological investigations links high dietary red meat and processed meat 5.1 Tea and coffee extracts consumption with a higher risk of human cancers, including breast cancer (Farvid et al., 2018), colorectal cancer (Wang et al., 2015), Tea polyphenols are known for their inhibitory effects on HAAs over and gastric cancer (Andersen, Halekoh, Tjønneland, Vogel, & Kopp, two decades and are widely used as an alternative marinade for meat 2019). Other studies highlighted that consumption of processed meat cooking (Table 1). In a chemical model system, Weisburger, Nagao, (50 g/day) increased the probability of some cancers, such as prostate Wakabayashi, and Oguri (1994) observed a 62–85% decline in PhIP by 4%, 18% for colonic, 9% for breast, and 19% for pancreatic (Wolk, and MeIQx levels after addition of green tea and black tea as well as 2017). However, weak asssociation was reported by other research theaflavin gallate and epigallocatechin 3-O-gallate (EGCG) followed by works between HAAs intake and cancer incidence, including colorec- heating at 160◦C, while both HAAs were reduced by 3.2–75% upon tal and prostate cancer (Chen et al., 2020; Ollberding, Wilkens, Hen- addition of green tea catechins as well as EGCG, luteolin, quercetin, or derson, Kolonel, & Le Marchand, 2012; Sander, Linseisen, & Rohrmann, caffeic acid into creatine-glycine/phenylalanine model system heated 2011). So, it is clear that this issue needs further investigation to be at 128◦C/2 hr (Oguri, Suda, Totsuka, Sugimura, & Wakabayashi, 1998). clarfied. In a later study, the purified extracts of green tea and black tea were In vitro and in vivo studies demonstrated that HAAs were highly reported to reduce the HAAs formation in a dose-dependent manner mutagenic toward Salmonella typhimurium andwerealsomutagenic in ground beef (Weisburger et al., 2002). In a bonito meat model sys- toward mammalian cells (Sugimura, Wakabayashi, Nakagama, & Nagao, tem (100◦C/24 hr or 48 hr), Kato, Harashima, Moriya, Kikugawa, and 2004). However, substantial differences were observed in the muta- Hiramoto (1996) also reported that 5% green tea extract and 0.5% genic activity among different types of HAAs. Thus, weaker mutagenic- EGCG solution could reduce, respectively, the formation of HAAs by a itywasexhibitedbyPhIP,AαC, and MeAαC compared to IQ, MeIQ, maximum of 30 and 50%. Similarly, the addition of selenium to green CAO ET AL. 141 2017 2002 2012 2010 2013 2016 2000 2007 2016 (Continues) 2020 2002 2014 2017 Weisburger et al., Cheng et al., Jamali et al., Amantana et al., Yao et al., Keskekoglu & Uren, Keskekoglu & Uren, Haskaraca et al., Rounds et al., Gibis & Weiss, C ◦ C ◦ the polyphenol extracts 70 for oven-roasted chicken extracts 45 for elderberry (only in thecaseofPhIP) Se 46 at 220 and 23 for white beef, and 37 for oven-roasting chicken Dose-related inhibition with 75 at 160 Dose-related inhibition with 16-18 for green and oolong, 60–83, 21–56, and 41–68 Sabally et al., No inhibition 46 for deep-fat fried beef and 65 and 5151 and 49 90 and 57 C α C 75–85 Quelhas et al., α mutagenicity bacterial mutagenicity PhIP being reduced most norharman, PhIP, and A MeIQx PhIP and A PhIP and MeIQx 70 for apple and grape seed Total polar HAAs 30–87 Balogh et al., HAAs HAAs including IQ, harman, PhIPMeIQx Total HAAs Total HAAs 65 for charcoal-barbecuing IQ and Ames test for PhIP and MeIQx C Total HAAs, with the level of ◦ C/45 s) in ◦ C/5 min/each ◦ C/6 min/each C/10 min/each C/4 min/each ◦ ◦ ◦ C/3 min, 80% steam) C/27 min) ◦ ◦ sunflower oil and steam cooking in an oven (160 side side (230 charcoal-barbecuing, or deep-fat frying side side 180–200 charcoal-barbecuing, or deep-fat frying Pan-frying (190 Oven roasting, pan cooking, Wood charcoal-grilled Oven roasting, pan cooking, Boiling Pan-frying Grilled at 200 nuggets meatballs meatballs Ground beef patties Frying Ames test for bacterial Green tea Chicken burgers and Chicken Beef patties Beef and chicken Beef patties Fried at 160 or 220 Beef Pan-frying at Beef patties Fried at 210 Beef patties Inhibitory effects of different treatments or additives on formation of HAAs in cooked meat tea (rich in and black tea selenate, seleno-DL-cysteine, seleno-L-methionine, and L-Se-methylselenocysteine tea extract tea extract (w/o emulsion) and 1.5% of rosemary extract in sunflower oil extract polyphenols) tea extract grape seed, and pineapple extracts TreatmentPurified extracts of green Sodium selenite, sodium FoodIncorporation of 3% green Cooking method1% of green, oolong, or white HAAs/mutagenicity3% of apple and olive extracts Inhibition (%)0.8% of grape seed extract Reference 0.5% pomegranate seed Grape seed extract Beef and chicken Rosa rugosa Marinating with 1% green 0.1% of apple, elderberry, 1% oleoresin rosemary Ground beef patties Fried at 225 0.3% apple peel extract Beef patties Pan-frying PhIP, 4,8-DiMeIQx, and TABLE 1 142 CAO ET AL. 2010 2019 2015 2005 2008 2008 2019 2010 2011 2010 2018 2019 Smith, 2011 2018 2017 Lu et al., Lee et al., Jung et al., Smith et al., Sepahpour et al., Suleman et al., Viegas et al., Awney & Sindi, onion, garlic, red >> chili, paprika, black pepper, and tomato 14–100 78 From 21 to 95 74–99 and 42–100 88 90 for black beer 62 for beef100 for chicken MeIQx, PhIP, and Norharman 75, 55, and 100 Ahn & Grun, Total HAAs 44 Oz, PhIP and MeIQx 88 and 43 Melo et al., MeIQx and PhIP 92 and 85 Puangsombat & Polar and nonpolar HAAs Total HAAs Total HAAs Total HAAs Total HAAs Total HAAs PhIP and Trp-P-1 Cfor ◦ Cfor C ◦ ◦ C C/105 min IQ, harman, and norharman 39, 67, and 63 Teng et al., ◦ ◦ C/10 min Total HAAs 39 and 34 Puangsombat et al., ◦ C Total HAAs Ginger C/10 min) ◦ ◦ Cfor C/4 min/each ◦ ◦ C ◦ attain core temperature of 72 10 min/each side 10 min/side) side) (5 min/each side) (4 min/each side) 5 min each side Grilling (240 Grilling Charcoal-grilling Frying at 180 Frying (220 Grilling for 10–12 min to Pan-roasting at 200 Grilling meatballs Beef steak Beef Ground beef patties Pork meat Beef meatball Frying (200 Beef patties Cooking at 191 or 204 Beef Grilling Total HAAs 84 and 97 Mousa & Al-Khateeb, Lamb patties Beef steaks Beef and chicken extract Pork Pan-frying at 230 (Continued) Sonchus olearleu Caribbean containing rosemary a mixture of turmeric and lemon grass (1:1) 15 g/100 g) and black beer oregano rosemary extracts (0.5%) and clove as well as a ternary mixture of turmeric, red chilli, and clove Treatment1% oleoresin rosemaryCommercial marinade Ground beef patties Food2% rosemary extract Cooking at 200/210 Replacing the curry leaf with Cooking methodGinger (0.5–2.5%) HAAs/mutagenicity Inhibition (%)Minced garlic (5, 10, and Extra virgin olive oil Reference Pilsner, nonalcoholic pilsner, Black cumin, basil, and 10% and 20% ethanol Turmeric and fingerroot Beef patties Cooking at 204 Spices powder Beef and chicken Beer or wine Beef meat Frying at 180-200 Binary mixture of turmeric 0.5% TABLE 1 CAO ET AL. 143 tea extract enhanced the antimutagenic effect on IQ-induced muta- 49% for MeIQx, respectively, in grilled beef patties (200◦C/5 min/each genicity in Salmonella as demonstrated by Amantana et al. (2002). After side) (Rounds, Havens, Feinstein, Friedman, & Ravishankar, 2013). In marinating beef with 1% green tea extract for 6 hr and pan-frying a later study, the incorporation of 0.3% apple peel extract was shown at 180–200◦C/4 min/each side, Quelhas et al. (2010) found a signif- to inhibit the formation of PhIP, 4,8-DiMeIQx, and MeIQx by 60, 21 icant reduction in PhIP and AαC formation by 75 and 85%, respec- and 41%, respectively, when mixed thoroughly in beef patty, while they tively, while the levels of 4,8-DiMeIQx and MeIQx remained unaltered. were reduced to a greater extent (83, 56, and 68%) upon marinating However, after incorporation of 3% green tea extract into the cover- only on the surface, suggesting that the surface application can be a ing material of chicken burgers and chicken nuggets, followed by pan- useful approach to minimize the formation of HAAs (Sabally, Sleno, frying (190◦C/45 s) in sunflower oil and steam cooking in an oven Jauffrit, Iskandar, & Kubow, 2016). (160◦C/3 min, 80% steam), no significant inhibition of HAAs formation In addition to apple, grape seed extract was reported to effectively was shown (Haskaraca, Soncu, Kolsarici, Oz, & Juneja, 2017). Jamali inhibit HAAs in meat. By using a marinade mixture containing 0.8% of et al. (2016) studied the effect of Rosa rugosa tea (rich in polyphenols) grape seed extract (without emulsion) and 1.5% of rosemary extract in on inhibition of HAAs formation in beef patties fried at 160 or 220◦C, sunflower oil used to fry beef patties, Gibis and Weiss (2012) showed and reported an inhibition of 75 or 46% of total HAAs, respectively, a reduction in the level of PhIP and MeIQx, respectively, by 90 and with the level of PhIP being reduced most. In addition, several HAAs 57% owing to a higher antioxidant activity of the grape seed extract such as harman, norharman, Trp-P-1, and Trp-P-2 were also reduced in by twofold compared to the rosemary extract. On the contrary, Natale, beef patties fried at 220◦C. More recently, with addition of 1% of green Gibis, Rodriguez-Estrada, and Weiss (2014) found that the incorpora- tea, oolong tea, or white tea extract, Yao et al. (2020) demonstrated tion of grape seed extract into liposomal system was not as effective that all the three tea extracts could inhibit the formation of HAAs as grape seed extract in inhibiting HAAs formation in meat. Recently, including IQ, harman, norharman, PhIP, and AαC in wood charcoal- Keskekoglu and Uren (2017) evaluated the inhibition efficiency of grilled chicken (230◦C/27 min), with the white tea extract showing grape seed extract toward HAAs formation in beef and chicken meat- the highest inhibitory effect (23%) compared to control (basic spice balls during oven roasting, pan cooking, charcoal-barbecuing, or deep- marinade), followed by oolong tea extract (18%) and green tea extract fat frying, demonstrating that the highest reduction of 65 or 37% of (16%). In addition, coffee consumption was reported to alleviate the total HAAs could be, respectively, obtained upon marinating with 0.5% DNA damage induced by oxidative stress and Trp-P-2, respectively, by grape seed extract, followed by charcoal-barbecuing beef meatball 17 and 35% in human lymphocytes due to a 38% rise in superoxide dis- (charcoal at 380◦C) or oven-roasting chicken meatball (180◦C/27 min). mutase level (Bichler et al., 2007). Also, cacao liquor, a major ingredi- However, with 0.5% pomegranate seed extract, the same authors ent of chocolate and cocoa containing several polyphenolic compounds observed a reduction of total HAAs by 39 and 46% in charcoal- such as catechin, epicatechin, clovamide, procyanidins, quercetin, and barbecued and deep-fat fried beef meatball, respectively, while a much their glycosides, was shown to possess antimutagenic effect both in higher inhibition of total HAAs by 49 and 70% was shown for deep-fat vitro and in vivo (Yamagishi et al., 2000). fried and oven-roasted chicken meat balls (Keskekoglu & Uren, 2014).

5.2 Fruit extracts 6 INHIBITION OF SPICE/HERBS ON HAAS FORMATION It is well documented that fruits are rich in phytochemicals, especially polyphenols that are associated with strong antioxidant activity and Some spice/herbs are widely applied to cook with meat (Figure 5). improvement of human health. Thus, several studies have evaluated Among various spices/herbs used for marinating meat, rosemary is the inhibitory effect of fruit extracts on the formation of HAAs in meat the most commonly used due to its polyphenols including carnosic during cooking (Table 1). For instance, Britt, Gomaa, Gray, and Booren acid, carnosol, and rosmarinic acid (Table 1). For instance, Balogh, Gray, (1998) reported a reduction in PhIP level by 93 and 87% through Gomaa, and Booren (2000) reported a decrease in the formation of inhibition of lipid oxidation upon adding cherry tissues from two tart total polar HAAs (IQ, MeIQ, MeIQx, DiMeIQx, and PhIP) by 30–87% varieties (rich in isoflavones and anthocyanins) into ground beef pat- in fried ground beef patties (225◦C/10 min/each side) marinated with ties prior to frying (170◦C/8 min/each side). The extracts (0.1%) from 1% oleoresin rosemary, while in a later study, Ahn and Grun (2005) fur- four different fruits (apple, elderberry, grape seed, and pineapple) were ther illustrated that 1.0% oleoresin rosemary could inhibit both polar compared by Cheng et al. (2007) to evaluate their inhibitory efficiency and nonpolar HAAs with a reduction of MeIQx by 75%, PhIP by 55%, on HAAs formation in fried beef patties (210◦C/6 min/each side). Com- and norharman by 100% in ground beef cooked at 200/210◦C for pared to the control, both apple and grape extracts were shown to 10 min/each side. On the contrary, following addition of rosmarinic be the most effective in reducing the total HAAs content (PhIP and acid or rosemary powder, no significant inhibition of norharman and MeIQx) by ∼70%, with elderberry reducing only PhIP formation by harman was observed in fried beef patties (191/204◦C for 5/7.5 min 45% and pineapple showing no inhibitory effect. The addition of a rel- each side) by Tsen, Ameri, and Smith (2006), probably caused by a low atively higher level of apple and olive extracts (3% each) was reported proportion of rosmarinic acid/rosemary powder (0.02–0.3%) used in to show a maximum inhibition of 65 and 51% for PhIP as well as 51 and this study as compared to 1% rosemary extract in the above studies. 144 CAO ET AL.

FIGURE 5 Some spice/herbs are applied to inhibit HAAs formation

Nevertheless, a decline in the level of polar HAAs such as MeIQx and In a study dealing with comparison of the inhibitory effects of five Asian PhIP by 64–70% and 48–64% was shown for rosmarinic acid, respec- spices (galangal, fingerroot, turmeric, cumin, and coriander seed) on tively, as well as 57–69% and 66–77% for rosemary powder, with both HAAs formation in cooked beef patties (204◦C/10 min), Puangsombat, possessing antimutagenicity toward S. typhimurium at a higher cook- Jirapakkul, and Smith (2011) demonstrated that turmeric and finger- ing temperature (204◦C). Similarly, commercial marinade Caribbean root (a Thai spice rich in flavonoids) were the most effective spices in containing rosemary was found to be more effective in inhibiting inhibiting total HAAs contents by 39 and 34%, respectively, with the total HAAs content by 88% in grilled beef steak (204◦C/5 min/each inhibition effects being correlated well with their total phenolic con- side) than herb marinade (72%) and southwest marinade (57%) tent and 2,2-diphenyl-1-picrylhydrazyl scavenging activity. Similarly, (Smith, Ameri, & Gadgil, 2008). In another study, Puangsombat and Jinap, Iqbal, and Selvam (2015) showed that 4.0 g of turmeric could Smith (2010) compared the inhibitory efficiency of different rosemary reduce the content of IQ by 82 ng in 100 g grilled beef (300◦C/3 or extracts obtained using 100% water and 10–40% ethanol in water on 4 min), followed by curry leaves (78.5 ng) and lemon grass (44.5 ng), HAAs formation in beef patties cooked at 191 and 204◦C for 5 min while the torch ginger was the most efficient in mitigating MeIQx for- each side, and demonstrated that both 10 and 20% ethanol rosemary mation by 83 ng. In another study, a rise in HAAs inhibition from 21 to extracts (0.5%) were the most effective in inhibiting MeIQx (up to 92%) 95% was shown to replace the curry leaf with a mixture of turmeric and PhIP (up to 85%) at both cooking temperatures, which may be due and lemon grass (1:1) on beef meat prior to grilling (240◦C/10 min) to the synergistic effects of rosmarinic acid, carnosol, and carnosic acid (Sepahpour et al., 2018). Similarly, a binary mixture of turmeric and obtained at a higher proportion with 10 and 20% ethanol as the extrac- clove as well as a ternary mixture of turmeric, red chilli, and clove tion solvent. Also, the addition of 2% rosemary extract was shown to were shown to reduce the total HAAs contents by 84 and 97%, respec- inhibit PhIP formation by 62% in beef shawerma as well as both PhIP tively, both of which were the most efficient among different combina- and Trp-P-1 by 100% in grilled chicken (Awney & Sindi, 2010). tions of various spices including turmeric, black pepper, red chili, cin- Turmeric, a popular spice rich in curcumin, bisdemethoxycurcumin, namon, and clove. The high inhibition efficiency was attributed to the and demethoxycurcumin, was reported to be as effective as rosemary. presence of curcumin, capsaicin, and eugenol in turmeric, red chili, and CAO ET AL. 145 clove, respectively. In addition, a higher antioxidant activity of these ing the formation of 4,8-DiMeIQx in pork or beef meat, respectively. three spices compared to the other ones may also contribute to this Similarly, a total of six marinades containing beer and white wine (with- inhibitory effect (Mousa & Al-Khateeb, 2017). out/with alcohol) alone or in combination with spices/herbs (rosemary, Ginger is another most widely used spice either alone or in combina- red chili pepper, garlic, ginger, and thyme) were reported to reduce the tion with garlic. For instance, Suleman et al. (2019) demonstrated that total amount of HAAs, with a combination of beer and spices/herbs ginger (0.5–2.5%) possesses the highest efficiency in inhibiting the for- showing the highest inhibition (90%) (Viegas, Amaro, Ferreira, & Pinho, mation of both polar and nonpolar HAAs (74–99% and 42–100%) in 2012). Comparatively, beer marinades were more efficient in mitigat- charcoal grilled lamb patties (10–12 min to attain core temperature of ing the HAAs formation than white wine marinades, while the wine 72◦C), followed by cinnamon, Chinese prickly ash, red chili, cumin, and without alcohol was better than the wine with alcohol in inhibiting black pepper, with the inhibition efficiency by all the six spices added HAAs formation. More recently, Vidal et al. (2020) further pointed out separately ranging from 46 to 99% for polar HAAs and 31 to 100% for that unfiltered beer-based marinades were effective in reducing lipid nonpolar HAAs. Similarly, among various spices such as ginger, onion, oxidation and Maillard reaction products in grilled beef and moose garlic, red chili, paprika, black pepper, and tomato evaluated for HAAs (200–250◦C for 25 min). inhibition efficiency, ginger powder was the most effective in reduc- Some other plant extracts were also reported to reduce total HAAs ing total HAAs content in fried beef and chicken meatballs (180◦C) (Lu, by 12–100% in chicken breast and 42–100% in beef by using 0.5% Kuhnle, & Cheng, 2018), while tomato and ginger showed a maximum hawthorn extract (Tengilimoglu-Metin, Hamzalioglu, Gokmen, & Kizil, reduction in MeIQx (77 and 69%), 4,5-DiMeIQx (80 and 71%), and PhIP 2017), while 1% artichoke extract could reduce total HAAs by 25– (79 and 66%) (Khan et al., 2017). Nevertheless, all the spices did show 98% in beef and 14–95% in chicken breast (Tengilimonglu-Metin & significant reduction in total HAAs content in meat samples. In addition Kizil, 2017). Also, a reduction in PhIP by 40 and 52%, respectively, with to ginger, garlic is also used in many culinary preparations and highly 10 mg/mL of lingonberry leaf extract and 2.5 mg/mL of bamboo leaf valued for its ability to alleviate many human diseases including dia- extract in a chemical meat model system (Rackauskiene, Pukalskas, betic and hypercholesterolemia. With an aim to investigate the poten- Fiore, Troise, & Venskutonis, 2019), and a decrease in IQ, harman, tial of organosulfur compounds in garlic to inhibit HAAs formation in and norharman by 39, 67, and 63% with 0.5% Sonchus olearleu extract meat during cooking, Shin, Rodgers, Gomaa, Strasburg, and Gray (2002) in pan-fried pork (230◦C/105 min), respectively, were reported (Teng added minced garlic cloves (4.8–16.7%) and several garlic-related sul- et al., 2019). fur compounds (0.67 mM) separately onto ground beef patties prior to frying (225◦C for 10 min/side) and observed a decline in HAAs contents by 71% and 22–81%, respectively. However, the addition of minced 7 INHIBITORY EFFECT OF POLYPHENOLS ON garlic (5, 10, and 15 g/100 g) to ground beef patties inhibited HAAs HAAS FORMATION formation by 14–100% during frying (220◦C/10 min/side) (Jung, Lee, Park,Dong,&Shin,2010). Some other spices such as black cumin, basil, Although the plant/spice/herb extracts possess the ability to exert and oregano were also reported to inhibit the formation of total HAAs synergistic effects, it is difficult to correlate the observed effects by 44% in beef meatball (200◦C/4 min/each side) as well as Trp-P-1 by to single functional compound for elucidation of structure–activity 39% and 13% in beef meat, respectively (Damasius, Venskutonis, Ferra- relationship. Several reports have demonstrated the inhibition effects cane, & Fogliano, 2011;Oz,2019). Also, by spreading extra virgin olive of HAAs by flavonoids, isoflavones, and phenolic acids as well as oil on beef steaks prior to pan-roasting at 200◦C (5 min/each side), a lycopene, EGCG, theaflavin 3,3′-digallate, and conjugated linoleic reduction in total HAAs content by 78% was shown, which might be acid (Figure 6). For instance, Weisburger, Dolan, and Pittman (1998) due to the presence of phenolic antioxidants in olive oil (Lee, Dong, showed a dose-dependent inhibition of PhIP-induced mutagenicity Jung, & Shin, 2011). in S. typhimurium by caffeine, lycopene, daidzein, and genistein, with

In recent years, the use of beer-based marinades without or the inhibitory concentration for 50% reduction of mutagenicity (IC50) with spices/herbs has become increasingly popular due to their high being 126, 271, 243, and 94 μg/mL, respectively. Compared to buty- polyphenol content. For instance, Melo, Viegas, Petisca, Pinho, and Fer- lated hydroxyl anisole (BHA), α-tocopherol, diallyl disulphide, eugenol, reira (2008) demonstrated, respectively, a decline in PhIP and MeIQx and four sugars (glucose, fructose, sucrose, and lactose), both EGCG levels by 88% and 43% after 6 hr marinating of beef meat with beer, 88 and naringenin were demonstrated to exert higher PhIP inhibition and 33% with red wine, followed by frying at 180–200◦C (4 min/each effect (99 and 98%) in a model system (Moon & Shin, 2013). Similarly, side). In a study dealing with evaluating the effects of three different nine different flavonoids (250–5000 μg/mL) were shown to exhibit beer varieties pilsner, nonalcoholic pilsner, and black beer on charcoal- a significant dose-dependent inhibition effect on PhIP formation in grilled pork meat, Viegas, Moreira, and Ferreira (2015) reported that all a chemical model system with the IC50 values ranging from 160 to the beer marinades were capable of minimizing total HAAs with black 4251 μg/mL and the inhibition effect followed the order: homoorien- beer showing the highest inhibition effect (90%). Also, a strong corre- tine > orientine > vitexin > isovitexin > luteolin > apigenin > isorham- lation was shown between the HAAs inhibitory effect and antioxidant netin > fisetin > hesperetin (Figure 5). Also, the IC50 of flavonoids activity of beer marinades. Interestingly, in the above two studies, the correlated well with the corresponding antioxidant activity, suggesting addition of black beer or beer marinade alone was capable of inhibit- that their inhibitory effects on PhIP are mainly caused by scavenging 146 CAO ET AL.

FIGURE 6 Chemical structures of polyphenols inhibiting HAAs formation

of free radicals generated in the reaction system (Zhang, Luo, Shao, lacetaldehyde (Gibis, 2016). An isotope-labeling study has confirmed Yu, & Wang, 2014). However, in a later study, Zhu, Zhang, Wang, Chen, that the generation of adducts between EGCG and phenylacetalde- and Zheng (2016) studied the inhibitory effects of eight flavonoids hyde could reduce the formation of PhIP (Cheng et al., 2009). In (0.2 mM) on total HAAs and PhIP formation in beef patties roasted addition, several studies have also shown the formation of 8/6-C-(E- at 230◦C/10 min/each side, and reported a reduction of 55–70% in phenylethenyl)polyphenol-type adducts, especially with quercetin, api- total HAAs content as well as 60–80% in PhIP through the formation genin, kaempferol, and luteolin (Figure 5) (Cheng et al., 2008;Zhu of adducts by flavonoids with phenylacetaldehyde, a key intermediate et al., 2016). From the structural point of view, flavones and flavonols in PhIP formation, but not by radical scavenging mechanism. The are more potent enzyme inhibitors involved in HAAs activation than antioxidant-independent mechanism of inhibition of HAAs formation flavanones, isoflavones, and chalcones, while among flavonols and in both model system and beef patties was clearly demonstrated in two flavanones, the parent compounds possessing the highest inhibition earlier studies by Cheng et al. (2007)andChengetal.(2009), with the effect can depend on number and position of hydroxyl groups (Eden- former reporting that polyphenols such as theaflavin 3,3′-digallate, epi- harder, Rauscher, & Platt, 1997). More specifically, polyphenols pos- catechin gallate, rosemarinic acid, and naringenin (Figure 5) were capa- sessing two hydroxyl groups at the meta position of aromatic ring ble of simultaneously inhibiting the formation of PhIP, MeIQx, and 4,8- are the most efficient inhibitors against the activation of HAAs, but DiMeIQx, while the latter revealing that both EGCG and its per acetate the presence of carboxylic or alkyl groups as substituents in the aro- (acetylated derivative of EGCG) could effectively reduce the PhIP for- matic ring slightly reduced the inhibitory effect (Gibis, 2016). Also, mation through inhibition of 90% phenylacetaldehyde. Also, a binary by increasing the polarity through introduction of more hydroxyl mixture of 0.05% chlorogenic acid and luteolin (1:1) present in cumin groups could reduce antimutagenic activity, while through reduction of spice was reported to inhibit 1,5,6-TMIP by 100% in roast beef patties hydroxyl groups by methyl etherification could restore the antimuta- (230◦C/10 min/each side), while a 1:1 mixture of rutin and protocate- genic potency (Edenharder, von Petersdorff, & Rausher, 1993). More- chuic acid (star anise) exerted synergistic inhibitory effects on harman, over, the aromatic rings C and A are not practically important to exert norharman, and MeIQx as well as a 2:1 mixture of p-coumaric acid and antimutagenicity, and the presence of two hydroxyl groups in ortho ferulic acid (chili pepper) on MeIQx (Zeng, Li, He, Qin, & Chen, 2016). and para positions may fail to provide inhibition effect on HAAs (Eden- harder et al., 1993). A planar structure in the vicinity of carbonyl groups may also play a pivotal role in antimutagenicity (Hatch, Lightstone, & 8 STRUCTURE–ACTIVITY RELATIONSHIP OF Colvin, 2000). HAAS INHIBITION BY POLYPHENOLS Many studies on evaluation of antimutagenic effect have con- cluded that polyphenols inhibit enzymes responsible for activation of The inhibitory effects of polyphenols on HAAs formation in both HAAs in organisms, especially cytochrome P450 reductase, which is model and meat systems are mainly due to (a) scavenging of free rad- involved in one-electron transfer N-oxidation (amino group) of HAAs icals and/or (b) trapping of reactive carbonyl species such as pheny- to form N-hydroxy ion (Dashwood et al., 1999; Hammons et al., CAO ET AL. 147

1999; Hatch et al., 2000; Hernaez, Xu, & Dashwood, 1997). If the tamination in food but it is also important to link them with cancer– cytochrome P450 reductase fails to be scavenged, N-hydroxy ion fur- human interactive studies. Thus, human monitoring to examine the ther undergoes O-acetylation to generate N-acetoxy amine catalyzed changes associated with HAAs exposure may prove beneficial. Public by N-acetyltransferases (Gibis, 2016). The high reactivity of N-acetoxy health must address necessary steps with programs and schemes at amine results in the formation of nitrenium ion of exocyclic amine public portfolio in this direction. It is also important to have follow-ups group, which is a critical metabolite responsible for toxicity and DNA for public health awareness and to monitor the shifts and changes in damage. food trends, especially in terms of consumer preferences and habits.

ORCID 9 PERSPECTIVE TRENDS AND FUTURE Jesus Simal-Gandara https://orcid.org/0000-0001-9215-9737 CHALLENGES Jianbo Xiao https://orcid.org/0000-0003-2666-9717

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