Carcinogenic Heterocyclic Amines Research Articles

Inhibitory action of antimicrobial peptides against the formation of carcinogenic and mutagenic heterocyclic amines in meat

Thermal processing of meat leads to the development of Maillard's reaction intermediates, and carcinogenic toxicants. For the first time, the effectiveness of three (HX-12 A, HX-12B and HX-12C) antimicrobial peptides (AMPs) against the formation of heterocyclic amines (HAs) in chemical and meat model systems. The results showed that AMPs especially 12 A and 12C have strong metal chelation potential (48 and 40 % at 1 mg/ml) and antioxidant activity (35 and 25 % at 1 mg/ml), respectively, which were endorsed by their secondary structure (FTIR analysis) in terms of high β-sheets (1628 cm−1 and 1672 cm−1) in those AMPs. UPLC-MS analysis revealed that 12 A and 12C were the most capable AMPs in MeIQx and PhIP-producing chemical models, respectively, whereas 12B promoted the HAs formation even higher than control. In particular, 12C AMP significantly (P < 0.05) decreased the most abundant carcinogenic HAs (PhIP) up to 90 % at 9 mg/100 g of fresh meat, whereas 12 A inhibited up to 80 % of mutagenic HAs at same level compared to control and 12B. Low Field Nuclear Magnetic Resonance (LF-NMR) test showed that inhibitory effect of 12 A and 12C was mediated by means of retaining water (lower T22 and T23 relaxation time) inside the macromolecules. This favorable effect was also evidenced by significantly enhanced tryptophan fluorescent intensity. Finally, based on correlation and principle component analysis, the mechanism of action has been proposed. These outcomes recommend that 12 A and 12C are potential AMPs for the attenuation of HAs in thermally processed meat-based products.

Carboxyl-functionalized covalent organic frameworks for the efficient adsorption of foodborne heterocyclic aromatic amines

The development of sorbents with high sensitivity and specificity for the effective extraction and assessment of carcinogenic heterocyclic aromatic amines (HAAs) in thermally processed foods is of utmost significance for food safety monitoring. Herein, we report the design and synthesis of a carboxyl-functionalized covalent organic framework (COF), TpPa-(COOH)2, through the regulation of carboxyl modification and crystallinity. The resulting flower-like TpPa-(COOH)2 exhibited excellent crystallinity and microporosity in an eclipsed stacking structure. Compared to TpPa, the introduction of carboxyl moieties in TpPa-(COOH)2 provided additional binding sites and significantly enhanced adsorption affinity for the 16 target analytes, despite having a smaller BET surface area. The adsorption of HAAs by TpPa-(COOH)2 followed the pseudo-second-order model and exhibited rapid kinetics (10–30 min). The experimental data demonstrated a strong fit with the Freundlich isotherm model, resulting in a maximum adsorption capacity of HAAs ranging from 1.8 to 155.8 mg/g. Additionally, the presence of interfering compounds only caused a slight reduction in both the equilibrium adsorption capacity and HAAs recovery. Notably, TpPa-(COOH)2 maintained its effective adsorption performance even after three adsorption–desorption cycles. Theoretical calculations indicated that the rapid binding of HAAs to TpPa-(COOH)2 could be attributed to the joint effects of electrostatic interaction, π–π interaction, C–H–π interaction, lone pair–π interaction, and hydrogen bonding. This adsorbent exhibits a notable enhancement in both adsorption capacity and mass transfer rates for the adsorption of HAAs, surpassing the performance of the reported adsorbents. This highlights its substantial potential for the precise detection of HAAs within food systems.

The influence of heat treatment type on the fat component and heterocyclic aromatic amines formation in minced poultry meat products

In this study the influence of heat treatment type on the change in the fatty acid composition, indices and parameters of fat oxidation, the level of heterocyclic amines formation in the chopped poultry ready-to-eat products enriched with ω‑3 fatty acids and an antioxidant complex were studied. The composition of ingredients and recipes of ready-to-eat products are developed with consideration of the medical and biological requirements for the diets of oncological patients. These ready-to-eat products feature some antioxidant substances in their composition that can bind free radicals, and provide for a reduction in the risk of carcinogens formation during the manufacturing process. The heat treatment was run in several ways, also called as modes — cooking in a microwave oven (MW), cooking in a convection oven in the “convection” mode with preliminary short-term roasting, steam cooking. For comparison, the conventional, i. e. not enriched food sample was used as a control one. The introduction of ω‑3 fatty acids into the food formulation made it possible to change the fatty acid composition towards increasing the proportion of polyunsaturated fatty acids (PUFAs). It was found that the profile of fatty acids was influenced by both the ingredients of the product and the type of its heat treatment. The joint use of a PUFA source and a complex of antioxidants made it possible to obtain a ready-to-eat product with a high level of ω‑3; and to ensure the ratio of ω‑6 group acids: ω‑3 ratio amounts to 1–2:1. Heat treatment of enriched semi-finished products by microwave cooking and by steam cooking showed a lesser effect on the change in the content and composition of polyunsaturated fatty acids — the loss of fatty acids was 1.2% and 2.8%, respectively, while in the “convection” cooking mode with preliminary roasting this loss was equal to 3.5%. It was found that the antioxidant complex in the composition of the food product and gentle heat treatment methods cause less lipid peroxidation and the formation of carcinogenic heterocyclic aromatic amines (HAA) during the food manufacturing process.

Carbonyl-trapping by phenolics and the inhibition of the formation of carcinogenic heterocyclic aromatic amines with the structure of aminoimidazoazaarene in beef patties

Carcinogenic heterocyclic aromatic amines (HAAs) with the structure of aminoimidazoazaarene (PhIP, MeIQx, IQ, and MeIQ) are produced by reaction of creatin(in)e, ammonia, and reactive carbonyls (phenylacetaldehyde, acrolein, and crotonaldehyde). In an attempt to provide efficient methodologies for HAA reduction in beef patties, this study: identified phloroglucinol as the most efficient phenolic to reduce HAA formation (76–96% inhibition); isolated and characterized by NMR and MS phloroglucinol/phenylcetaldehyde and phloroglucinol/acrolein adducts; and determined by LC-MS/MS adduct formation in beef patties treated with phloroglucinol. Obtained results suggested that addition of trihydroxyphenols (including phloroglucinol) to beef patties should decrease HAA formation. This was confirmed by both immersing beef patties in apple (or pear) juice before cooking (>90% inhibition) and including wheat bran in patty recipe. All these results confirm the key role of reactive carbonyls in the formation of carcinogenic HAAs and propose carbonyl-trapping as a way for controlling HAA formation in food products.

Determination of 2-amino-1-methyl-6-phenylimidazole [4, 5-b] pyridine (PhIP) and its precursors and possible intermediates in a chemical model system and roast pork

PhIP (2-amino-1-methyl-6-phenylimidazole [4, 5-b] pyridine) is a carcinogenic heterocyclic aromatic amine often generated in thermal processing of food. Methods for PhIP and its precursors and possible intermediates determination in chemical model system and roast pork were established based on HPLC-Q-Orbitrap-HRMS and GC-MS. Results showed that the linearity of 8 targets was good in a certain concentration range (R2 ≥ 0.992). LODs and LOQs were in the range of 0.3–15 μg/kg and 1–50 μg/kg, respectively. Under the model system, the recoveries of 8 target compounds ranged from 86.3% to 119.2%, with relative standard deviations (RSDs) of 0.5–6.9%. The established method was applied to 8 targets determination in roast pork, with recoveries ranging from 87.1% to 107.3% and RSDs in the range of 1.2–7.8%. The developed methods are accurate and fast, which are suitable for PhIP and its precursors and possible intermediates analysis in chemical model system and actual meat products.

Advancing metabolic networks and mapping updated urinary metabolic fingerprints after exposure to typical carcinogenic heterocyclic aromatic amines

Heterocyclic aromatic amines (HAAs) were not only present in cooked foods and cigarette smoke, but also measured in airborne particles and diesel-exhaust particles. Typical HAAs have been reported to induce carcinogenicity and metabolic disturbances, but how these hazardous compounds interfere with metabolic networks by regulating metabolic pathways and fingerprinting signature metabolites as biomarkers remains ambiguous. We developed an advanced strategy that adopted chemical isotope labeling ultrahigh-performance liquid chromatography coupled to quadrupole-Orbitrap high-resolution mass spectrometry for urinary nontargeted metabolomics analysis to gain new insight into in vivo physiological responses stimulated by exposure to typical HAAs. Rats were orally administered with a single dose of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) (1 and 10 mg/kg bw) and their D3-isotopic compounds, respectively, and urine samples were then continuously collected within 36 h. Metabolomics data were acquired and processed by classical multivariate statistical analysis, while urinary metabolites were further identified and characterized according to mass spectrometric fragmentation rules, time- and dose-dependent profiles, and calibration of synthesized standards. We monitored 23 and 37 urinary metabolites as the biotransformation products of PhIP and MeIQx, respectively, and first identified demethylated metabolites of PhIP, tentatively named 2-amino-6-phenylimidazo[4,5-b]pyridine, and dihydroxylation products of classical HAAs as short-term biomarkers of exposure to further unravel the metabolic networks. In addition, our findings revealed that both HAAs significantly disturb histidine metabolism, arginine and proline metabolism, tryptophan metabolism, pyrimidine metabolism, tricarboxylic acid cycle, etc. Furthermore, we found that histamine, methionine, alanine, and 4-guanidinobutanoic acid could be considered potential characteristic biomarkers for the oncogenicity or carcinogenicity of both PhIP and MeIQx and screened their specific key pivotal metabolites. The current metabolomics approach is applicable in mapping updated urinary metabolic fingerprints and identifying potential specific biomarkers for HAAs-induced early tumorigenesis.

Inhibitory and antioxidative capacity of nutmeg extracts on reduction of lipid oxidation and heterocyclic amines in pan-roasted beef patties

Identification and inhibition of mutagenic and carcinogenic heterocyclic amines (HCAs) from pan-roasted beef patties were performed by adding (0.02%) tertiary butyl hydroquinone (TBHQ) and (0.05%) ethanol-extracted nutmeg (ENE) using HPLC and principal component analysis. Ten HCAs, including six polar and four non-polar, were assessed. The addition of (0.05%) ENE significantly (P < 0.05) reduced the cooking loss and shrinkage of patties during cooking and reduced the total formation HCAs by 73.97%, which proved the significant (P < 0.05) inhibitory effect as a natural antioxidant against lipid oxidation and HCA formation compared to TBHQ. The DPPH radical-scavenging activity, total phenolic content, and available active metabolites of ENE were estimated. Furthermore, a positive correlation was observed between pH, level of thiobarbituric acid reactive substances, and HCA formation in both the groups. TBHQ and ENE were significant HCAs inhibitors (P < 0.001), but ENE showed resilient oxidative stability during refrigeration storage. Therefore, ENE can be used to reduce HCAs formation in pan-roasted beef patties.

Induction of CYP3A4 mRNA by cooked food-derived carcinogenic heterocyclic aromatic amines in human HPL-A3 cells

Induction of CYP3A4 mRNA by cooked food-derived carcinogenic heterocyclic aromatic amines in human HPL-A3 cells

Selective Impedimetric Chemosensing of Carcinogenic Heterocyclic Aromatic Amine in Pork by dsDNA-Mimicking Molecularly Imprinted Polymer Film-Coated Electrodes.

Inspired by the easy intercalation of quinoxaline heterocyclic aromatic amines (HAAs) in double-stranded DNA (dsDNA), we synthesized a nucleobase-functionalized molecularly imprinted polymer (MIP) as the recognition unit of an impedimetric chemosensor for the selective determination of a 2-amino-3,7,8-trimethyl-3H-imidazo[4,5-f]quinoxaline (7,8-DiMeIQx) HAA. HAAs are generated in meat and fish processed at high temperatures. They are considered to be potent hazardous carcinogens. The MIP film was prepared by potentiodynamic electropolymerization of a pre-polymerization complex of two adenine- and one thymine-substituted bis(2,2′-bithien-5-yl)methane functional monomer molecules with one 7,8-DiMeIQx template molecule, in the presence of the 2,4,5,2′,4′,5′-hexa(thiophene-2-yl)-3,3′-bithiophene cross-linking monomer, in solution. The as-formed MIP chemosensor allowed for the selective impedimetric determination of 7,8-DiMeIQx in the 47 to 400 μM linear dynamic concentration range with a limit of detection of 15.5 μM. The chemosensor was successfully applied for 7,8-DiMeIQx determination in the pork meat extract as a proof of concept.

UiO-66 metal-organic frameworks/gold nanoparticles based substrates for SERS analysis of food samples

Recently, metal-organic frameworks (MOFs) based substrates have shown great potential for the quantitative analysis of food samples by surface-enhanced Raman scattering (SERS) due to their unique properties. Herein, we developed two UiO-66 MOFs/gold nanoparticles (AuNPs) based substrates by self-assembly, including UiO-66/AuNPs suspension substrate and UiO-66(NH2)/AuNPs/Nylon-66 flexible membrane substrate, for quantitative analysis of complex food samples by SERS. UiO-66/AuNPs suspension substrate was prepared for SERS-based determination of a carcinogenic heterocyclic amine in barbecue meat. UiO-66(NH2)/AuNPs/Nylon-66 membrane substrate was fabricated for the simultaneous separation, enrichment, and in situ analysis of Sudan Red 7B in chilli products. The heterocyclic amine and Sudan dye in real samples could be detected and quantified with the recoveries of 82.3–110% and 84.5–114% and relative standard deviations (RSDs) of 3.1–11.0% and 1.9–5.6% (n = 3) by use of these two substrates, respectively. These two UiO-66/AuNPs based substrates combined molecular enrichment and SERS activity, achieving excellent analytical accuracy and widening SERS application in practical food safety analysis.

Impact of manipulation of glycerol/diol dehydratase activity on intestinal microbiota ecology and metabolism.

Glycerol/diol dehydratases (GDH) are enzymes that catalyse the production of propionate from 1,2-propanediol, and acrolein from glycerol. Acrolein reacts with dietary carcinogenic heterocyclic amines (HCA), reducing HCA mutagenicity, but is itself also an antimicrobial agent and toxicant. Gut microbial GDH activity has been suggested as an endogenous acrolein source; however, there is limited information on the potential of the intestinal microbiota to have GDH activity, and what impact it can have on the intestinal ecosystem and host health. We hypothesized that GDH activity of gut microbiota is determined by the abundance and distribution of GDH-active taxa and can be enhanced by supplementation of the GDH active Anaerobutyricum hallii, and tested this hypothesis combining quantitative profiling of gdh, model batch fermentations, microbiota manipulation, and kinetic modelling of acrolein formation. Our results suggest that GDH activity is a common trait of intestinal microbiota shared by a few taxa, which was dependent on overall gdh abundance. Anaerobutyricum hallii was identified as a key taxon in GDH metabolism, and its supplementation increased the rate of GDH activity and acrolein release, which enhanced the transformation of HCA and reduced fermentation activity. The findings of this first systematic study on acrolein release by intestinal microbiota indicate that dietary and microbial modulation might impact GDH activity, which may influence host health.

Takashi Sugimura: In Memoriam (1926–2020)–A Personal Perspective

![][1] Takashi Sugimura was a pioneer in cancer research and a figure recognized internationally for his seminal contributions to the understanding of mutagenicity and chemical carcinogenesis. Rather than focusing on the many accolades, honors, and influential positions that he held,

Development of Biological Response Modifiers Based on Unique Medicinal Chemical Strategy

Chemical biology and structural development studies performed at The University of Tokyo during 1977-2020 are outlined chronologically. The studies are divided into three parts, i.e., (i) chemical biology of chemical carcinogenesis and molecular design of anti-tumor agents, (ii) structural development studies on biological response modifiers, and (iii) studies on so-called dramatype drug discovery focusing on pharmacological chaperones and protein knockdown-inducers. The first part describes analysis of DNA modification by Glu-P-1, which is a typical carcinogenic heterocyclic amine found in cooked foods, as well as molecular design of DNA-cleaving agents with anti-tumor properties. The second part deals with structural development studies of nuclear receptor ligands and various biological response modifiers derived from thalidomide, including the ligand superfamily concept and the multi-template strategy. The third part describes pharmacological chaperones that should be useful for the treatment of protein misfolding diseases, including Niemann-Pick type C disease and retinitis pigmentosa, and a protein knockdown strategy aimed at degradation of neurodegenerative-disease-causing polyglutamic aggregative proteins.

Blueberry, raspberry, and strawberry extracts reduce the formation of carcinogenic heterocyclic amines in fried camel, beef and chicken meats

Heterocyclic amines (HCAs) are toxic products from the Maillard reaction that form from the reaction of sugars, amino acids and creatine/creatinine when cooking protein rich food. In this work, commonly consumed meats in Saudi Arabia (camel, beef and chicken) were fried under conditions resembling home cooking. The effect of marinades made of blueberry, raspberry and strawberry were tested separately on meat at different marinating times (1, 6, 12, 24h, at 4 °C) before frying. The marinades caused an overall reduction of HCAs. The decrease was more noticeable with long marination time ≥ 6h. The reduction of individual HCAs, after 24h marinades, was 91–100% for pyridines; 40–67% for β-carbolines; and 100% for quinoxalines, quinolines, α-carbolines and ɣ-carbolines, although the latter three were seldomly detected in this study. An increase, up to 2 times, on the formation of the studied quinoxalines was observed in every meat and marination for no more than 1h. Therefore, longer marinating times with berry extracts, from 6h, are recommended over those below (1h).

Shrimp as a substantial source of carcinogenic heterocyclic amines

In the present work, fifteen mutagenic/carcinogenic heterocyclicamines (HAs)were studied in cooked Caridean shrimp (pink) and Penaeid shrimp (tiger, white and brown). The cooking methods were used as stir-frying, broiling and steaming under controlled temperature and time, and HAs determination was performed by SPE/UPLC-ESI-MS/MS. HAs 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-Amino-1,6-dimethyl-imidazo[4,5-b]pyridine (DMIP), 1-Methyl-9H-pyrido[3,4-b]indole (Harman) and 9H-pyrido[3,4-b]indole (Norharman) were identified (0.05–22.48 ng/g) in all stir-fried and broiled shrimp, whereas 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) was only found (0.08–0.35 ng/g) in stir-fried shrimp. HAs 2-Amino-3,7,8-trimethyl-imidazo[4,5-f]quinoxaline (7,8-DiMeIQx) and, α-carbolines 2-Amino-9H-pyrido[2,3-b]indole (AαC) and 2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeAαC), γ-carbolines 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-Amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and δ-carbolines 2-Amino-6-methyldipyrido[1,2-α:3́,2́-d]imidazole (Glu-P-1) and 2-Aminodipyrido[1,2-α:3́,2́-d]imidazole (Glu-P-2) were not detected or found below quantification limit. Brown shrimp (stir-fried) appeared to be more contaminated which constitutes total HAs (81.93 ng/g) followed by pink (70.41 ng/g), tiger (53.02 ng/g) and white (33.57 ng/g). Steaming method does not yield any HAs, and the cause might be elucidate that shrimp were not directly in contact with cooking pan or fire which affect the HAs formation. Food precursors (protein, moisture, fat, creatine and glucose) were also measured in raw and cooked shrimp to investigate the influence on HAs formation. Creatine (3.85 mg/g) and glucose (0.43 mg/g) were found at higher concentrations in brown shrimp, generates high amounts of HAs. Our findings have illustrated that the cooking method, shrimp types and precursors are the main contributors to the formation of HAs. The outcomes from this work could be applied to estimate the HAs human intake globally and add to steaming cooking method in such types of food products that diminish the risk of HAs exposure, and thus to get healthier food quality and security.

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.

Mitigation of heterocyclic aromatic amines in cooked meat. Part I: Informed selection of antioxidants based on molecular modeling

This work aimed to develop a method permitting an informed choice of antioxidants to reduce carcinogenic heterocyclic aromatic amine (HAA) formation during proteinaceous food cooking. Therefore, a three-step approach was developed. First, the most promising antioxidants were selected using molecular modeling approaches. For this, analog design was used to highlight the most suitable antioxidants based on their diversification potential using bioisosteric replacement. Then, structure activity relationship studies allowed drawing the relevant properties for inhibiting HAA formation and explained partly the inhibitory activity. Secondly, the approved antioxidants were tested in ground beef patties to assess their inhibitory properties against HAA formation. Resveratrol was found to be the most efficient as it totally inhibited MeIQ and reduced MeIQx and PhIP formation by 40 and 70%, respectively. Finally, natural ingredients rich in these antioxidants were evaluated. Oregano was found to totally inhibit MeIQ formation and to reduce by half MeIQx and PhIP formation.

Sulforaphane suppresses carcinogenesis of colorectal cancer through the ERK/Nrf2‑UDP glucuronosyltransferase 1A metabolic axis activation.

The long pre-cancerous state of colorectal cancer (CRC) provides an opportunity to prevent the occurrence and development of CRC. The detoxification of CRC food-borne carcinogenic heterocyclic amines is highly dependent on UDP glucuronosyltransferase 1A (UGT1A)-mediated glucuronidation. Sulforaphane (SFN), a phytochemical, possesses antioxidant, anti-inflammatory and anticarcinogenic effects on the prevention of CRC. Previous studies revealed that SFN upregulates the expression of UGT1A. The aim of the present study was to investigate the regulatory mechanism of SFN-induced UGT1A upregulation and provide novel understanding on the basic research and chemoprevention of CRC. In the present study, the viability and proliferation of CRC cells (HT-29 and SW480) treated with SFN were assessed by MTT, colony formation and EdU assays. Flow cytometry was used to detect the cell cycle arrest and apoptosis of cells treated with different concentrations of SFN. The motility of cells was determined by wound healing and Transwell assays. Nuclear factor, erythroid 2 like 2 (Nrf2) short hairpin RNA (shRNA) and negative control shRNA lentiviruses were used for cell transfection. Reverse transcription-quantitative polymerase chain reaction and western blotting were employed to verify the role of Nrf2 in SFN-induced UGT1A. HT-29 and SW480 cells were divided into a control, an SFN and a PD98059 [an extracellular signal-regulated kinase (ERK) inhibitor] + SFN group. Western blotting detected the protein levels of Nrf2 and UGT1A. Intracellular levels of reactive oxygen species (ROS) were detected using a reactive oxygen assay kit. The results revealed that SFN inhibits cell proliferation and colony formation, promotes apoptosis, and reduces the migratory ability of CRC cells. The phosphorylation of ERK induced by SFN promoted Nrf2 accumulation. Furthermore, a significant increase in the levels of UGT1A was observed, which coincided with SFN-induced upregulation of Nrf2 levels in nuclear fractions. Pretreatment with PD58059 reversed the SFN-induced subcellular translocation of Nrf2 and the expression of UGT1A. In addition, SFN-induced high levels of ROS in CRC cells may be associated with the ERK signaling pathway. Collectively, these results indicated that SFN inhibited the proliferation of CRC cells and upregulated the expression of UGT1A in CRC cells via the ERK/Nrf2 signaling pathway.

Biological significance of aminophenyl-β-carboline derivatives formed from co-mutagenic action of β-carbolines and aniline and o-toluidine and its effect on tumorigenesis in humans: A review

Norharman exists in cigarette smoke and cooked foods and is non-mutagenic among Salmonella strains but mutagenic to S. typhimurium TA98 and YG1024 in the presence of S9 mix and aniline and o-toluidine. Co-mutagenesis of β-carbolines and aniline and o-toluidine occurs through the formation of novel mutagenic aminophenyl-β-carboline derivatives including 9-(4’-aminophenyl)-9H-pyrido[3,4-b]indole [aminophenylnorharman] (APNH)] and 9-(4’- amino-3’-methylphenyl)-9H-pyrido[3,4-b]indole [aminomethylphenylnorharman] (AMPNH)]. Since humans are often simultaneously exposed to β-carbolines and aniline and o-toluidine, their effects on humans should be clarified. The most potent of these, APNH, induced both point mutations and small deletions in the liver and colon of gpt delta transgenic mice. Major APNH-induced mutations in the liver occurred at a G:C base pair, suggesting that APNH-DNA adducts (dG-C8-APNH) are potentially involved in these mutations. Furthermore, APNH induced hepatic and colon tumors harboring K-ras, β-catenin, and Apc mutations in F344 rats, with high incidence. Mutations at G:C base pairs were predominant, similar to those in the in vivo mutation assay using gpt delta mice. Moreover, APNH detected in human urine samples obtained from both healthy volunteers on a normal diet and inpatients receiving parenteral alimentation; therefore, APNH can be considered an endogenous carcinogen contributing to tumorigenesis. Exposure levels of these aminophenyl-β-carboline derivatives may be lower than those of carcinogenic heterocyclic amines (HCAs) including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx); however, their health risks in terms of tumorigenesis may be comparable owing to stronger genotoxic effects of APNH rather than HCAs. This review summarized APNH mutagenicity/carcinogenicity, and its in vivo formation. Moreover, the effect on tumorigenesis in humans also discussed.

Potential carcinogenic heterocyclic aromatic amines (HAAs) in foodstuffs: Formation, extraction, analytical methods, and mitigation strategies.

During the heat treatment of proteinaceous food, heterocyclic aromatic amines (HAAs), a kind of strong mutagens/carcinogens are formed. HAAs can be classified into two major groups based on the heating temperature, which are thermic HAAs generally formed in 150 to 300°C and pyrolytic HAAs produced above 300°C. This review focuses on the formation mechanisms of HAAs and identifies different mechanisms of the formation of HAAs in foodstuffs. Moreover, an overview of the available extraction, purification methods, and instrumental analytical methods in the last two decades is shown to determine the HAAs in various foodstuffs. Finally, based on the factors that affect the formation of HAAs in heat-processed foodstuffs, such as the cooking method, food type, the recipe, and the content of substances with enhancing or inhibiting effects on the formation of HAAs, this review also highlights the most promising strategies for mitigating HAAs, which include adjusting cooking methods or process conditions, adding natural product extracts, antioxidants or other compounds, or reasonable selection of types of foodstuff. The review intends to provide a broad but comprehensive understanding of the formation, extraction, purification, analytical methods, and possible mitigation strategies for isolated and identified HAAs.