Piper auritum ethanol extract is a potent antimutagen against food-borne aromatic amines. Mechanisms of action and chemical composition.

An ethanol extract of Piper auritum leaves (PAEE) inhibits the mutagenic effect of three food-borne aromatic amines (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP); 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx); 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx) in the TA98 Salmonella typhimurium strain. Preincubation with MeIQx demonstrated in mutagenesis experiments that inhibition of Cytochrome P450 (CYP), as well as direct interaction between component(s) of the plant extract with mutagens, might account for the antimutagenic observed effect. Gas chromatography/mass spectrometry analysis revealed that safrole (50.7%), α-copaene (7.7%), caryophyllene (7.2%), ß-pinene (4.2%), γ-terpinene (4.1%) and pentadecane (4.1%) as the main components of PAEE. Piper extract and safrole were able to inhibit the rat liver microsomal CYP1A1 activity that participates in the amines metabolism, leading to the formation of the ultimate mutagenic/ molecules. According to this, safrole and PAEE inhibited MeIQx mutagenicity but not that of the direct mutagen 2-nitrofluorene. No mutagenicity of plant extract or safrole was detected. This study show that PAEE and its main component safrole are associate with the inhibition of heterocyclic amines activation due in part to the inhibition of CYP1A subfamily activity.

Formation and prediction of heterocyclic amines and N-nitrosamines in smoked sausages using back propagation artificial neural network.

BACKGROUND: Heterocyclic amines (HAs) and N-nitrosamines (NAs) are formed easily during the thermal processing of food, and epidemiological studies have demonstrated that consuming HAs and NAs increases the risk of cancer. However, there are few studies on the application of back propagation artificial neural network (BP-ANN) models to simultaneously predict the content of HAs and NAs in sausages. This study aimed to investigate the effects of cooking time and temperature, smoking time and temperature, and fat-to-lean ratio on the formation of HAs and NAs in smoked sausages, and to predict their total content based on the BP-ANN model. RESULTS: With an increase in processing time, processing temperature and fat ratio, the content of HAs and NAs in smoked sausages increased significantly, while the content of HA precursors and nitrite residues decreased significantly. The optimal network topology of the BP-ANN model was 5-11-2, the correlation coefficient values for training, validation, testing and all datasets were 0.99228, 0.99785, 0.99520 and 0.99369, respectively, and the mean squared error value of the best validation performance was 0.11326. The bias factor and the accuracy factor were within acceptable limits, and the predicted values approximated the true values, indicating that the model has good predictive performance. CONCLUSION: The contents of HAs and NAs in smoked sausages were significantly influenced by the cooking conditions, smoking conditions and fat ratio. The BP-ANN model has high application value in predicting the contents of HAs and NAs in sausages, which provides a theoretical basis for the suppression of carcinogen formation. © 2024 Society of Chemical Industry.

Emerging challenges and efficacy of polyphenols-proteins interaction in maintaining the meat safety during thermal processing.

Polyphenols are well documented against the inhibition of foodborne toxicants in meat, such as heterocyclic amines, Maillard's reaction products, and protein oxidation, by means of their radical scavenging ability, metal chelation, antioxidant properties, and ability to form protein-polyphenol complexes (PPCs). However, their thermal stability, low polarity, degree of dispersion and polymerization, reactivity, solubility, gel forming properties, low bioaccessibility index during digestion, and negative impact on sensory properties are all questionable at oil-in-water interface. This paper aims to review the possibility and efficacy of polyphenols against the inhibition of mutagenic and carcinogenic oxidative products in thermally processed meat. The major findings revealed that structure of polyphenols, for example, molecular size, no of substituted carbons, hydroxyl groups and their position, sufficient size to occupy reacting sites, and ability to form quinones, are the main technical points that affect their reactivity in order to form PPCs. Following a discussion of the future of polyphenols in meat-based products, this paper offers intervention strategies, such as the combined use of food additives and hydrocolloids, processing techniques, precursors, and structure-binding relationships, which can react synergistically with polyphenols to improve their effectiveness during intensive thermal processing. This comprehensive review serves as a valuable source for food scientists, providing insights and recommendations for the appropriate use of polyphenols in meat-based products.

Risk Assessment of Polycyclic Aromatic Hydrocarbons and Heterocyclic Aromatic Amines in Processed Meat, Cooked Meat and Fish-Based Products Using the Margin of Exposure Approach.

Background: The objective of this study is to assess the risk of exposure of polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HCAs) in meat and fish-based products marketed in Malaysia using the margin of exposure (MOE) approach. Methods: Benchmark Dose (BMD) software was used to model the BMD at a lower end of a one-sided 95% confidence interval with a 10% incremental risk (BMDL10) of PAHs and HCAs from different target organ toxicities. The MOEs of PAHs and HCAs in meat and fish-based products were determined by utilising the calculated BMDL10 values and estimated daily intake of meat and fish-based products from published data. Results: The calculated BMDL10 values of PAHs (i.e. benzo[a]pyrene [BaP] and fluoranthene [FA]) and HCAs (i.e. 2-amino-3,8,dimethylimidazo[4,5-f]quinoxaline [MeIQx] and 2-amino-1-methyl-6-phenylimidazo[4,5,6]pyridine [PhIP]) ranged from 19 mg/kg bw/day to 71,801 mg/kg bw/day. The MOE of BaP ranged from 41,895 to 71,801 and that of FA ranged from 19 to 1412. As for MeIQx and PhIP, their MOEs ranged from 6,322 to 7,652 and from 2,362 to 14,390, respectively. Conclusion: The MOEs of FA, MeIQx and PhIP were lower than 10,000, indicating a high concern for human health and therefore demanding effective risk management actions.

Heterocyclic amines reduce insulin-induced AKT phosphorylation and induce gluconeogenic gene expression in human hepatocytes.

Heterocyclic amines (HCAs) are well-known for their mutagenic properties. One of the major routes of human exposure is through consumption of cooked meat, as certain cooking methods favor formation of HCAs. Recent epidemiological studies reported significant associations between dietary HCA exposure and insulin resistance and type II diabetes. However, no previous studies have examined if HCAs, independent of meat consumption, contributes to pathogenesis of insulin resistance or metabolic disease. In the present study, we have assessed the effect of three HCAs commonly found in cooked meat (2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline [MeIQ], 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline [MeIQx], and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [PhIP]) on insulin signaling and glucose production. HepG2 or cryopreserved human hepatocytes were treated with 0-50 µM of MeIQ, MeIQx, or PhIP for 3 days. Treatment of HepG2 cells and hepatocytes with MeIQ and MeIQx resulted in a significant reduction in insulin-induced AKT phosphorylation, suggesting that HCA exposure decreases hepatic insulin signaling. HCA treatment also led to significant increases in expression of gluconeogenic genes, G6PC and PCK1, in both HepG2 and cryopreserved human hepatocytes. Additionally, the level of phosphorylated FOXO1, a transcriptional regulator of gluconeogenesis, was significantly reduced by HCA treatment in hepatocytes. Importantly, HCA treatment of human hepatocytes led to increases in extracellular glucose level in the presence of gluconeogenic substrates, suggesting that HCAs induce hepatic glucose production. The current findings suggest that HCAs induce insulin resistance and promote hepatic glucose production in human hepatocytes. This implicates that exposure to HCAs may lead to the development of type II diabetes or metabolic syndrome.

The effect of the rs1799931 G857A (G286E) polymorphism on N-acetyltransferase 2-mediated carcinogen metabolism and genotoxicity differs with heterocyclic amine exposure.

Human N-acetyltransferase 2 (NAT2) is subject to genetic polymorphism in human populations. In addition to the reference NAT2*4 allele, two genetic variant alleles (NAT2*5B and NAT2*7B) are common in Europe and Asia, respectively. NAT2*5B possesses a signature rs1801280 T341C (I114T) single-nucleotide polymorphism (SNP), whereas NAT2*7B possesses a signature rs1799931 G857A (G286E) SNP. NAT2 alleles possessing the T341C (I114T) or G857A (G286E) SNP were recombinant expressed in yeast and tested for capacity to catalyze the O-acetylation of the N-hydroxy metabolites of heterocyclic amines (HCAs). The T341C (I114T) SNP reduced the O-acetylation of N-hydroxy-2-amino-3-methylimidazo [4,5-f] quinoline (N-OH-IQ), N-hydroxy-2-amino-3,8-dimethylimidazo [4,5-f] quinoxaline (N-OH-MeIQx) and N-hydroxy- 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (N-OH-PhIP), whereas the G857A (G286E) SNP reduced the O-acetylation of N-OH-IQ and N-OH-MeIQx but not N-OH-PhIP. The G857A (G286E) SNP significantly (p < 0.05) reduced apparent Km toward N-OH-PhIP but did not significantly (p > 0.05) affect apparent Vmax. Cultures of DNA repair-deficient Chinese hamster ovary (CHO) cells transfected with human CYP1A2 and NAT2*4, NAT2*5B or NAT2*7B alleles were incubated with various concentrations of IQ, MeIQx or PhIP and double-stranded DNA damage and reactive oxygen species (ROS) were measured. Transfection with human CYP1A2 did not significantly (p > 0.05) increase HCA-induced DNA damage and ROS over un-transfected cells. Additional transfection with NAT2*4, NAT2*5B or NAT2*7B allele increased both DNA damage and ROS. The magnitude of the increases was both NAT2 allele- and substrate-dependent showing the same pattern as observed for the O-acetylation of the N-hydroxylated HCAs suggesting that both are mediated via NAT2-catalyzed O-acetylation. The results document the role of NAT2 and its genetic polymorphism on the O-acetylation and genotoxicity of HCAs.

Comprehensive Analyses of Advanced Glycation end Products and Heterocyclic Amines in Peanuts during the Roasting Process.

Advanced glycation end products (AGEs) and heterocyclic amines (HAs) are two kinds of important harmful products formed simultaneously during the thermal processing of proteinaceous food. In this paper, the effect of roasting conditions on the formation of AGEs and HAs, as well as active carbonyl intermediates in common peanut (C-peanut) and high-oleic acid peanut (HO-peanut) was studied simultaneously for the first time. In general, with the increase in roasting temperature (160-200 °C) and time, the contents of AGEs, HAs and active carbonyl intermediates (i.e., glyoxal (GO) and methylglyoxal (MGO)) significantly increased in peanuts. Four kinds of HAs (i.e., AαC, DMIP, Harman and Norharman) were observed in roasted peanuts, of which Harman and Norharman accounted for about 93.0% of the total HAs content after roasting for 30 min at 200 °C. Furthermore, a correlation analysis among AGEs (i.e., Nε-(1-Carboxymethyl)-L-lysine (CML) and Nε-(1-Carboxyethyl)-L-lysine (CEL)), HAs, GO and MGO was conducted. Most of these compounds showed an excellent positive linear relationship (p ≤ 0.001) with each other. The evident increase in GO and MGO contents implied an increase in not only the content of AGEs but also HAs. However, contents of AGEs and HAs showed no significant difference between roasted HO-peanut and C-peanut. This study would provide a theoretical basis for simultaneously controlling the levels of AGEs and HAs in thermal processed peanut foods.

Synthesis of New Azetidine and Oxetane Amino Acid Derivatives through Aza-Michael Addition of NH-Heterocycles with Methyl 2-(Azetidin- or Oxetan-3-Ylidene)Acetates.

In this paper, a simple and efficient synthetic route for the preparation of new heterocyclic amino acid derivatives containing azetidine and oxetane rings was described. The starting (N-Boc-azetidin-3-ylidene)acetate was obtained from (N-Boc)azetidin-3-one by the DBU-catalysed Horner-Wadsworth-Emmons reaction, followed by aza-Michael addition with NH-heterocycles to yield the target functionalised 3-substituted 3-(acetoxymethyl)azetidines. Methyl 2-(oxetan-3-ylidene)acetate was obtained in a similar manner, which was further treated with various (N-Boc-cycloaminyl)amines to yield the target 3-substituted 3-(acetoxymethyl)oxetane compounds. The synthesis and diversification of novel heterocyclic amino acid derivatives were achieved through the Suzuki-Miyaura cross-coupling from the corresponding brominated pyrazole-azetidine hybrid with boronic acids. The structures of the novel heterocyclic compounds were confirmed via 1H-, 13C-, 15N-, and 19F-NMR spectroscopy, as well as HRMS investigations.

ß-Carboline Alkaloids in Soy Sauce and Inhibition of Monoamine Oxidase (MAO).

Monoamine oxidase (MAO) oxidizes neurotransmitters and xenobiotic amines, including vasopressor and neurotoxic amines such as the MPTP neurotoxin. Its inhibitors are useful as antidepressants and neuroprotectants. This work shows that diluted soy sauce (1/3) and soy sauce extracts inhibited human MAO-A and -B isozymes in vitro, which were measured with a chromatographic assay to avoid interferences, and it suggests the presence of MAO inhibitors. Chromatographic and spectrometric studies showed the occurrence of the ß-carboline alkaloids harman and norharman in soy sauce extracts inhibiting MAO-A. Harman was isolated from soy sauce, and it was a potent and competitive inhibitor of MAO-A (0.4 µM, 44 % inhibition). The concentrations of harman and norharman were determined in commercial soy sauces, reaching 243 and 52 µg/L, respectively. Subsequently, the alkaloids 1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid (THCA) and 1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid (MTCA) were identified and analyzed in soy sauces reaching concentrations of 69 and 448 mg/L, respectively. The results show that MTCA was a precursor of harman under oxidative and heating conditions, and soy sauces increased the amount of harman under those conditions. This work shows that soy sauce contains bioactive ß-carbolines and constitutes a dietary source of MAO-A and -B inhibitors.

Application of cellulose- and chitosan-based edible coatings for quality and safety of deep-fried foods.

Excessive oil uptake and formation of carcinogens, such as acrylamide (AA), heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons (PAHs), during deep-frying are a potential threat for food quality and safety. Cellulose- and chitosan-based edible coatings have been widely applied to deep-fried foods for reduction of oil uptake because of their barrier property to limit oil ingress, and their apparent inhibition of AA formation. Cellulose- and chitosan-based edible coatings have low negative impacts on sensory attributes of fried foods and are low cost, nontoxic, and nonallergenic. They also show great potential for reducing HCAs and PAHs in fried foods. The incorporation of nanoparticles improves mechanical and barrier properties of cellulose and chitosan coatings, which may also contribute to reducing carcinogens derived from deep-frying. Considering the potential for positive health outcomes, cellulose- and chitosan-based edible coatings could be a valuable method for the food industry to improve the quality and safety of deep-fried foods.

Synthesis of piperidine and pyrrolidine derivatives by electroreductive cyclization of imine with terminal dihaloalkanes in a flow microreactor.

We have successfully synthesized piperidine and pyrrolidine derivatives by electroreductive cyclization using readily available imine and terminal dihaloalkanes in a flow microreactor. Reduction of the substrate imine on the cathode proceeded efficiently due to the large specific surface area of the microreactor. This method provided target compounds in good yields compared to a conventional batch-type reaction. Furthermore, piperidine and pyrrolidine derivatives could be obtained on preparative scale by continuous electrolysis for approximately 1 hour.

Synthesis of a new series of pyrazolo[1,5-a]pyrimidines as CDK2 inhibitors and anti-leukemia.

Based on the structural study of previously known CDK2 inhibitors, a new series of pyrazolo[1,5-a]pyrimidine derivatives was designed and synthesized. The target compounds were biologically assessed as potent CDK2 inhibitors and promising anti-leukemia hits. The 7-(4-Bromo-phenyl)-3-(3-chloro/2-chloro-phenylazo)-pyrazolo[1,5-a]pyrimidin-2-ylamines 5 h and 5i revealed the best CDK2 inhibitory activity with comparable potency (IC50 = 22 and 24 nM, respectively) to that of dinaciclib (IC50 = 18 nM). Additionally, both analogues showed potent activities against CDK1, CDK5 and CDK9 at nanomolar concentrations (IC50 = 28-80 nM). The anti-leukemia screening of the target compounds showed strong to moderate cytotoxicity against the used leukemia cell lines (MOLT-4 and HL-60). Compound 5 h inhibited MOLT-4 and HL-60 by 1.4 and 2.3 folds (IC50 = 0.93 and 0.80 µM), respectively, compared to dinaciclib (IC50 = 1.30 and 1.84 µM). Furthermore, compound 5i was comparable to dinaciclib against MOLT-4 and exhibited twice its activity against HL-60. Besides, the cytotoxicity of the promising analogues on normal human blood cells indicated the safety of 5h and 5i as compared to the reference dinaciclib. The pharmacokinetic properties of 5h and 5i were predicted using ADME calculations revealing good oral bioavailability and high GI absorption. The molecular docking simulations indicated, as expected, that the dinaciclib analogues can well-accommodate the CDK2 binding site, forming a variety of interactions.

Effects of seasoning on the formation of heterocyclic amines and polycyclic aromatic hydrocarbons in meats: A meta-analysis.

Cooking improves digestibility, palatability, and microbiological profile of meats, but can produce compounds with carcinogenic potential, such as heterocyclic amines (HAs) and polycyclic aromatic hydrocarbons (PAHs). It has been shown that the formation of these compounds in meats can be inhibited by spiced marinades, but there is a complexity to check and compare the results of isolated studies with so many variables involved. Thus, this work aimed to review studies that evaluated the effects of spices on the formation of HAs and PAHs in meats according to cooking techniques and spice type. A meta-analysis with a random effect model was conducted using response ratios (R) to identify and summarize previous results and answer the research question. The use of spices before frying (R* = 0.52), grilling (R* = 0.63), or roasting (R* = 0.74) meat, and spicing with garlic and onion (R* = 0.57), pepper (R* = 0.63), and other spices with phenolic compounds (R* = 0.63), decrease the formation of HAs and PAHs, due to the antioxidant and electron transfer capacity. In this article, we discuss how the improvement of culinary techniques with the dissemination of knowledge about meat preparation conditions is an effective strategy for reducing the formation and ingestion of HAs and PAHs; this is important due to the growing evidence about the association between meat consumption and chronic diseases. This is the first systematic review with meta-analysis about this topic and can guide industry, food services, and population to improve the safety associated with meat consumption.

Heterocyclic Amine Formation in Grilled Chicken Depending on Body Parts and Treatment Conditions.

Heterocyclic amines (HCAs) carcinogenicity is known since the 1970's, but the exact way of their formation is still unclear. During these examinations different body parts (breast filet with and without skin, thigh filet without skin and full wing with skin) of chickens from the same Ross 308 strain were analyzed after grilling with the combination of 3-3 temperature and duration levels (150-180-210 °C and 2.5-5-10 min per side). Five different kinds of heterocyclic amines (HAR, NOR, MeIQx, 4,8-DiMeIQx and PhIP) were detected by HLPC-MS/MS. The results obtained from the present study confirm that, in general, the higher the temperature and longer the duration of the grilling the more HCAs will be generated. Grilling of chicken thigh without bones and skin resulted in lower amounts of HCAs generated in comparison to the grilling of chicken breast without skin. The presence of skin on the chicken breast increased the amounts of HCAs formed, especially if grilling was performed at high temperature for longer duration, especially at 210 °C for 10 min. In case of grilling the chicken wings, the amounts of HCAs formed were lower than observed in the breast.

The Inhibitory Effects of Heterotrigona Itama Honey Marinades on the Formation of Carcinogenic Heterocyclic Amines in Grilled Beef Satay.

Heterocyclic amines (HCAs) are carcinogenic food toxicants formed in cooked meats, which may increase the risk of cancer development in humans. Therefore, in this study, the effect of stingless bee honey from different botanical origins on the formation of HCAs in grilled beef satay was investigated. HCAs concentration in grilled beef satay was determined by using high performance liquid chromatography (HPLC). In total, six of the most toxigenic HCAs representing aminoimidazo-azaarenes (AIAs) (MeIQx, 4,8-DiMeIQx, and PhIP) and amino carbolines (norharman, harman, and AαC) groups were identified in all the beef samples investigated. A significant reduction in HCAs was observed in grilled beef marinated in honey as compared to beef samples marinated in table sugar (control), in which the reduction of 95.14%, 88.45%, 85.65%, and 57.22% was observed in gelam, starfruit, acacia, and Apis honey marinades, respectively. According to the partial least squares regression (PLS) model, the inhibition of HCAs in grilled beef was shown to be significantly correlated to the antioxidant activity (IC50) of the honey samples. Therefore, the results of this study revealed that the addition of stingless bee honey could play an important role in reducing HCAs in grilled beef.

The Quaternization Reaction of 5-O-Sulfonates of Methyl 2,3-o-Isopropylidene-ß-D-Ribofuranoside With Selected Heterocyclic and Aliphatic Amines.

The synthesis of N-((methyl 5-deoxy-2,3-O-isopropylidene-ß-D-ribofuranoside)-5-yl)ammonium salts are presented. To determine the effect of the nucleophile type and outgoing group on the quaternization reaction, selected aliphatic and heterocyclic aromatic amines reacted with: methyl 2,3-O-isopropylidene-5-O-tosyl-ß-D-ribofuranoside or methyl 2,3-O-isopropylidene-5-O-mesyl-ß-D-ribofuranoside or methyl 2,3-O-isopropylidene-5-O-triflyl-ß-D-ribofuranoside were performed on a micro scale. High-resolution 1H- and 13C-NMR spectral data for all new compounds were recorded. Additionally, the single-crystal X-ray diffraction analysis for methyl 2,3-O-isopropylidene-5-O-mesyl-ß-D-ribofuranoside and selected in silico interaction models are reported.

Heterocyclic amines in braised chicken may mainly infiltrate from reused marinade during braising, instead of thermic generation.

BACKGROUND: Sauce braised meat products are popular in Asia, although their complicated processing may lead to potential safety risks. Especially, how hazardous compounds are formed during their preparation is still unclear. In the present study, braised chicken breasts, which are a typical Chinese sauce braised meat product, were used to investigate the formation of heterocyclic amines (HCAs) during heat treatment. RESULTS: Precursor content (creatine and reducing sugar), HCA level and temperature were measured in different parts of the chicken breast at each processing stage. The results obtained showed that the increasing trends of total HCA content in different parts of chicken breast were not the same. Only total HCA content in the skin (4.93 ± 0.80 ng g-1 ) increased significantly after deep-frying. During braising, total HCA level in the skin was high (12.1-14.3 ng g-1 ) and relatively stable. However, total HCA content in pectoralis major muscle (3.90-7.40 ng g-1 ) and pectoralis minor muscle (1.44-5.31 ng g-1 ) was much lower than in the skin, and increased steadily with braising time. CONCLUSION: Braising is the main factor which affects HCA level in braised chicken. Combining the results of temperature and precursor content, a possible explanation for the large amount of HCAs in braised chicken is the gradual infiltration from reused marinade, instead of thermic generation. © 2019 Society of Chemical Industry.

Gut microbial beta-glucuronidase and glycerol/diol dehydratase activity contribute to dietary heterocyclic amine biotransformation.

BACKGROUND: Consuming red and processed meat has been associated with an increased risk of colorectal cancer (CRC), which is partly attributed to exposure to carcinogens such as heterocyclic amines (HCA) formed during cooking and preservation processes. The interaction of gut microbes and HCA can result in altered bioactivities and it has been shown previously that human gut microbiota can transform mutagenic HCA to a glycerol conjugate with reduced mutagenic potential. However, the major form of HCA in the colon are glucuronides (HCA-G) and it is not known whether these metabolites, via stepwise microbial hydrolysis and acrolein conjugation, are viable precursors for glycerol conjugated metabolites. We hypothesized that such a process could be concurrently catalyzed by bacterial beta-glucuronidase (B-GUS) and glycerol/diol dehydratase (GDH) activity. We therefore investigated how the HCA-G PhIP-N2-ß-D-glucuronide (PhIP-G), a representative liver metabolite of PhIP (2-Amino-1-methyl-6-phenylimidazo [4,5-b] pyridine), which is the most abundant carcinogenic HCA in well-cooked meat, is transformed by enzymatic activity of human gut microbial representatives of the phyla Firmicutes, Bacteroidetes, and Proteobacteria. RESULTS: We employed a combination of growth and enzymatic assays, and a bioanalysis approach combined with metagenomics. B-GUS of Faecalibacterium prausnitzii converted PhIP-G to PhIP and GDH of Flavonifractor plautii, Blautia obeum, Eubacterium hallii, and Lactobacillus reuteri converted PhIP to PhIP-M1 in the presence of glycerol. In addition, B-GUS- and GDH-positive bacteria cooperatively converted PhIP-G to PhIP-M1. A screen of genes encoding B-GUS and GDH was performed for fecal microbiome data from healthy individuals (n = 103) and from CRC patients (n = 53), which revealed a decrease in abundance of taxa with confirmed GDH and HCA transformation activity in CRC patients. CONCLUSIONS: This study for the first time demonstrates that gut microbes mediate the stepwise transformation of PhIP-G to PhIP-M1 via the intermediate production of PhIP. Findings from this study suggest that targeted manipulation with gut microbes bearing specific functions, or dietary glycerol supplementation might modify gut microbial activity to reduce HCA-induced CRC risk.

Xenobiotics Formed during Food Processing: Their Relation with the Intestinal Microbiota and Colorectal Cancer.

The colonic epithelium is exposed to a mixture of compounds through diet, among which some are procarcinogens, whereas others have a protective effect. Therefore, the net impact of these compounds on human health depends on the overall balance between all factors involved. Strong scientific evidence has demonstrated the relationship between nitrosamines (NA), heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons (PAHs), which are the major genotoxins derived from cooking and food processing, and cancer. The mechanisms of the relationship between dietary toxic xenobiotics and cancer risk are not yet well understood, but it has been suggested that differences in dietary habits affect the colonic environment by increasing or decreasing the exposure to mutagens directly and indirectly through changes in the composition and activity of the gut microbiota. Several changes in the proportions of specific microbial groups have been proposed as risk factors for the development of neoplastic lesions and the enrichment of enterotoxigenic microbial strains in stool. In addition, changes in the gut microbiota composition and activity promoted by diet may modify the faecal genotoxicity/cytotoxicity, which can be associated with a higher or lower risk of developing cancer. Therefore, the interaction between dietary components and intestinal bacteria may be a modifiable factor for the development of colorectal cancer in humans and deserves more attention in the near future.

Effect of Dietary Red Meat on Colorectal Cancer Risk-A Review.

Heme iron overload has been implicated as the main cause of the increased risk of cancer due to the consumption of red meat. However, fish and shellfish, teas, and spices contain up to five times more iron than red meat. There is insufficient evidence that iron intake in dietary red meat is the primary causal factor for colorectal cancer. In addition, harmful substances produced during the preparation of red meat, including heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs), N-nitroso compounds, and acrylamide, are extrinsic factors that increase carcinogenicity. HCAs are produced during the cooking of red meat, poultry meat, and fish. PAHs may also be produced during the cooking of diverse food groups, such as dairy products, fruits, vegetables, and cereals. The average daily intake of red meat among Korean individuals is 62 g; the amount of PAHs entering the body via red meat is less than the average amount of PAHs the body is exposed to in the air. Therefore, it is difficult to conclude that dietary red meat is the main cause of colorectal cancer. Rather, there may be an intricate influence of multiple factors, including fruit and vegetable intake, alcohol consumption, smoking, overweight, obesity, and stress.