Cited by 146Meat and Animal Product QualityNutritional Studies and DietAntioxidant Activity and Oxidative Stress

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Diet-induced endogenous formation of nitroso compounds in the GI tract

Kuhnle, Gunter G.C., Story, Giles W., Reda, Torsten, Mani, Ali R., Moore, Kevin P., Lunn, Joanne C., Bingham, Sheila A.·2007·Free Radical Biology and Medicine

DOI 10.1016/j.freeradbiomed.2007.03.011

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Abstract

Red or processed meat, but not white meat or fish, is associated with colorectal cancer. The endogenous formation of nitroso compounds is a possible explanation, as red or processed meat--but not white meat or fish--causes a dose-dependent increase in fecal apparent total N-nitroso compounds (ATNC) and the formation of nitroso-compound-specific DNA adducts. Red meat is particularly rich in heme and heme has also been found to promote the formation of ATNC. To investigate the underlying mechanism of ATNC formation, fecal and ileal samples of volunteers fed a high red meat or a vegetarian diet were analyzed for nitrosyl iron, nitrosothiols, and heme. To simulate the processes in the stomach, food homogenates and hemoglobin were incubated under simulated gastric conditions. Nitrosyl iron and nitrosothiols were significantly (p < 0.0001) increased in ileal and fecal samples after a high red meat diet compared with a vegetarian diet; significantly more nitrosyl iron than nitrosothiols was detectable in ileal (p < 0.0001) and fecal (p < 0.001) samples. The strong correlation between fecal nitrosyl iron and heme (0.776; p < 0.0001) suggested that nitrosyl heme is the main source of nitrosyl iron, and ESR confirmed the presence of nitrosyl heme in fecal samples after a high red meat diet. Under simulated gastric conditions, mainly nitrosothiols were formed, suggesting that acid-catalyzed thionitrosation is the initial step in the endogenous formation of nitroso compounds. Nitrosyl heme and other nitroso compounds can then form under the alkaline and reductive conditions of the small and large bowel.

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“Under alkaline conditions, nitric oxide may in part react with heme molecules [22], so that the nitrosyl heme is formed [20].”
Replacement of Nitrite in Meat Products by Natural Bioactive Compounds Results in Reduced Exposure to N‐Nitroso Compounds: The PHYTOME Project
Breda, S. G. J. V., Mathijs, K., Pieters, H., Sági‐Kiss, V., Kuhnle, G., Georgiadis, P., Saccani, G., Parolari, G., Virgili, R., Sinha, R. R., et al. (2021) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202001214 · Cited by 31
Reformulation of processed meat to attenuate potential harmful effects in the gastrointestinal tract – A review of current knowledge and evidence of health prospects
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Plant-Based Diet and Risk of Iron-deficiency Anemia. A Review of the Current Evidence and Implications for Preventive Strategies
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“Similarly, heme iron acts as a catalyst for the formation of nitrosamines (NOCs), which are recognised carcinogens according to the IARC [69].”
Inulin-fortification of a processed meat product attenuates formation of nitroso compounds in the gut of healthy rats
Thøgersen, R., Gray, N., Kuhnle, G., HECKE, T. V., SMET, S. D., Young, J. F., Sundekilde, U. K., Hansen, A. K., & Bertram, H. C. (2019) · Food Chemistry · doi:10.1016/j.foodchem.2019.125339 · Cited by 29
A study of the bioactive potential of seven neglected and underutilized leaves consumed in Brazil
de Souza, T. C. L., da Silveira, T. F. F., Rodrigues, M. I., Ruiz, A. L. T. G., Neves, D. A., Duarte, M. C. T., Cunha, E. C. E., Kuhnle, G., Ribeiro, A. B., & Godoy, H. T. (2021) · Food Chemistry · doi:10.1016/j.foodchem.2021.130350 · Cited by 29
The dual function of nitrite under stomach conditions is modulated by reducing compounds
Volk, J., Gorelik, S., Granit, R., Kohen, R., & Kanner, J. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.04.012 · Cited by 29
Gut microbiota can utilize prebiotic birch glucuronoxylan in production of short-chain fatty acids in rats
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Effect of dietary meat and fish on endogenous nitrosation, inflammation and genotoxicity of faecal water
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“This confirms the important contribution of haem to endogenous nitrosation (18).”
BackgroundMethodInfluential
Heme-Induced Biomarkers Associated with Red Meat Promotion of colon Cancer Are Not Modulated by the Intake of Nitrite
Chenni, F. Z., Taché, S., Naud, N., Guéraud, F., Hobbs, D. A., Kunhle, G. C. G., Pierre, F. H. F., & Corpet, D. E. (2013) · Nutrition and Cancer · doi:10.1080/01635581.2013.749291 · Cited by 26
“Nitrosyl heme is the main source of iron nitrosyl (44), which is consistent with the strong NO-scavenging activity of hemoglobin (47).”
Background
Relationships between gut microbiota, red meat consumption and colorectal cancer.
Diakité, M., Diakité, B., Koné, A., Balam, S., Fofana, D., Diallo, D., Kassogué, Y., Traoré, C. B., Kamaté, B., Ba, D. M., et al. (2022) · PubMed · Cited by 34
Effects of sodium nitrite reduction, removal or replacement on cured and cooked meat for microbiological growth, food safety, colon ecosystem, and colorectal carcinogenesis in Fischer 344 rats
Guéraud, F., Buisson, C., Promeyrat, A., Naud, N., Fouché, E., Bézirard, V., Dupuy, J., Plaisancié, P., Héliès‐Toussaint, C., Trouilh, L., et al. (2023) · npj Science of Food · doi:10.1038/s41538-023-00228-9 · Cited by 23
Epidemiology, Molecular Mechanisms, and Clinical Trials: an Update on Research on the Association Between Red Meat Consumption and Colorectal Cancer
Kossenas, K., & Constantinou, C. (2021) · Current Nutrition Reports · doi:10.1007/s13668-021-00377-x · Cited by 23
Dietary nitrite induces nitrosation of the gastric mucosa: the protective action of the mucus and the modulatory effect of red wine
Pereira, C., Barbosa, R. M., & Laranjinha, J. A. N. (2015) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2014.12.004 · Cited by 23
“6 × 10(2) M−2 s−1) [23,24] under similar experimental conditions [21] in particular at lower pH [23,25] and in presence of bicarbonate [26], such as found in the gastric environment.”
Using a dynamic artificial digestive system to investigate heme iron nitrosylation during gastro-intestinal transit
Pomélie, D. D. L., Santé-Lhoutellier, V., Sayd, T., Théron, L., & Gatellier, P. (2019) · Food Chemistry · doi:10.1016/j.foodchem.2018.12.094 · Cited by 23
Kiwifruit as a Modulator of DNA Damage and DNA Repair
Collins, A. R. (2013) · Advances in food and nutrition research · doi:10.1016/b978-0-12-394294-4.00016-x · Cited by 22
Recent Perspectives on the Relations between Fecal Mutagenicity, Genotoxicity, and Diet
Gratz, S. W., Wallace, R. J., & El-Nezami, H. S. (2011) · Frontiers in Pharmacology · doi:10.3389/fphar.2011.00004 · Cited by 20
“Different methods are used to illustrate the proportion of DNA remaining in the Comet Head (i.e., undamaged DNA) and in the Comet tail (i.e., excretion of less mutagenic stools in six volunteers compared to a high risk mixed diet (Kuhnlein et al., 1983).”
Diet Composition Is Associated with Endogenous Formation of N-Nitroso Compounds in Obese Men
Holtrop, G., Johnstone, A. M., Fyfe, C., & Gratz, S. W. (2012) · Journal of Nutrition · doi:10.3945/jn.112.158824 · Cited by 20
The effects of substituting red and processed meat for mycoprotein on biomarkers of cardiovascular risk in healthy volunteers: an analysis of secondary endpoints from Mycomeat
Farsi, D. N., Lara, J., Finnigan, T. J. A., Cheung, W., Muñoz-Muñoz, J., & Commane, D. M. (2023) · European Journal of Nutrition · doi:10.1007/s00394-023-03238-1 · Cited by 22
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Method
Inulin and milk mineral fortification of a pork sausage exhibits distinct effects on the microbiome and biochemical activity in the gut of healthy rats
Thøgersen, R., Castro-Mejía, J. L., Sundekilde, U. K., Hansen, L. H., Gray, N., Kuhnle, G., Jørgensen, N. R., Hansen, A. K., Nielsen, D. S., & Bertram, H. C. (2020) · Food Chemistry · doi:10.1016/j.foodchem.2020.127291 · Cited by 17
Dietary Nitrosamines from Processed Meat Intake as Drivers of the Fecal Excretion of Nitrosocompounds
Ruiz-Saavedra, S., Pietilä, T. K., Zapico, A., Reyes‐Gavilán, C. G. D. L., Pajari, A., & González, S. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c05751 · Cited by 20
“28,29 Unless otherwise stated, the chemicals were obtained from Sigma-Aldrich (Merck Life Science).”
Method
Induction of Colonic Aberrant Crypts in Mice by Feeding Apparent N-Nitroso Compounds Derived From Hot Dogs
Davis, M. E., Lisowyj, M. P., Zhou, L., Wisecarver, J. L., Gulizia, J. M., Shostrom, V., Naud, N., Corpet, D. E., & Mirvish, S. S. (2012) · Nutrition and Cancer · doi:10.1080/01635581.2012.650777 · Cited by 14
“Each set of results included thos e f r total ANC and for ANC after addition of mercuric chloride (HgCl2), a test for R SNO, or of potassium ferricyanide [K3Fe(CN)6], a test for nitrosyl iron compounds [RF eNO] (17).”
Method
The colon carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is actively secreted in the distal colon of the rat: an integrated view on the role of PhIP transport and metabolism in PhIP-induced colon carcinogenesis
Nicken, P., Schröder, B., von Keutz, A., Breves, G., & Steinberg, P. (2013) · Archives of Toxicology · doi:10.1007/s00204-012-1006-0 · Cited by 14
“…(e.g. endogenously formed N-nitroso compounds) (Bingham et al. 1996; Hughes et al. 2001; Bingham et al. 2002; Cross et al. 2003; Lewin et al. 2006; Kuhnle et al. 2007) and other risk factors (ethanol, tobacco and/or obesity among others) are responsible for the high colorectal cancer incidence…”
Background
In vitro digestion of nitrite and nitrate preserved fermented sausages – New understandings of nitroso-compounds’ chemical reactivity in the digestive tract
Keuleyan, E., Bonifacie, A., Sayd, T., Duval, A., Aubry, L., Bourillon, S., Gatellier, P., Promeyrat, A., Nassy, G., Scislowski, V., et al. (2022) · Food Chemistry X · doi:10.1016/j.fochx.2022.100474 · Cited by 13
“Those adducts generally promote mutagenesis, and through multiple reactions, may trigger carcinogenesis (Kuhnle et al., 2007; Van Hecke, Vanden Bussche, Vanhaecke, Vossen, Van Camp, & De Smet, 2014).”
Background
Nitrosative deamination of 2′-deoxyguanosine and DNA by nitrite, and antinitrosating activity of β-carboline alkaloids and antioxidants
Herraiz, T., & Galisteo, J. (2017) · Food and Chemical Toxicology · doi:10.1016/j.fct.2017.12.042 · Cited by 14
Synthesis and in vitro characterization of the genotoxic, mutagenic and cell-transforming potential of nitrosylated heme
Kostka, T., Fohrer, J., Guigas, C., Briviba, K., Seiwert, N., Fahrer, J., Steinberg, P., & Empl, M. T. (2020) · Archives of Toxicology · doi:10.1007/s00204-020-02846-8 · Cited by 12
Chemical effects of nitrite reduction during digestion of cured cooked and recooked meat on nitrosation, nitrosylation and oxidation
Bonifacie, A., Aubry, L., Sayd, T., Bourillon, S., Duval, A., Kombolo, M., Nassy, G., Promeyrat, A., Santé-Lhoutellier, V., & Théron, L. (2024) · Food Research International · doi:10.1016/j.foodres.2024.114969 · Cited by 11
El consumo de nitrato y su potencial efecto benéfico sobre la salud cardiovascular
Brayan Moreno, C., Karen Soto, O., & González, D. R. (2015) · Revista chilena de nutrición · doi:10.4067/s0717-75182015000200013 · Cited by 13
Detection of N ‐nitroso‐bile acids at 285 nm in reverse‐phase HPLC
Araki, Y., Mukaisyo, K.-I., Sugihara, H., Fujiyama, Y., & Hattori, T. (2008) · Journal of Separation Science · doi:10.1002/jssc.200800230 · Cited by 10
Iron and Cancer
Connor, J. R., & Lee, S. Y. (2010) · Humana Press eBooks · doi:10.1007/978-1-60761-627-6_21 · Cited by 9
A comparative analysis of heme vs non-heme iron administration: a systematic review and meta-analysis of randomized controlled trials
Ruelas, M. G., Alvarado‐Gamarra, G., Aramburú, A., Dolores-Maldonado, G. K., Rodríguez, K. C., Rojas-Limache, G., Díaz-Parra, C. D. P., & Lanata, C. F. (2024) · European Journal of Nutrition · doi:10.1007/s00394-024-03564-y · Cited by 9
Urinary Excretion of N-Nitroso Compounds in Rats Fed Sodium Nitrite and/or Hot Dogs
Zhou, L., Anwar, M. M., Zahid, M., Shostrom, V., & Mirvish, S. S. (2014) · Chemical Research in Toxicology · doi:10.1021/tx5000188 · Cited by 9
The association between meat and fish intake by preparation methods and breast cancer in the Carolina Breast Cancer Study (CBCS)
Omofuma, O. O., Steck, S. E., Olshan, A. F., & Troester, M. A. (2022) · Breast Cancer Research and Treatment · doi:10.1007/s10549-022-06555-x · Cited by 9
Understanding the microbiome: a primer on the role of the microbiome in colorectal neoplasia
Watson, K. M. (2020) · Annals of Gastroenterology · doi:10.20524/aog.2020.0467 · Cited by 9
“responsible for endogenous production of NOCs, accounting for approximately 45-75% of total NOC exposure [102].”
BackgroundInfluential
A comprehensive review on various carcinogenic aspects of N-nitrosopiperidine (NPIP)
Chaudhary, P., Singh, D., & Janmeda, P. (2024) · Phytochemistry Reviews · doi:10.1007/s11101-024-10000-w · Cited by 10
“Moreover, Kuhnle et al. (2007) reported the presence of nitrosyl heme in faeces and in ileum, generated by the nitrosation and nitrosylation, and might promotes the generation of diazoacetate, a very reactive alkylating agent.”
Metal-Free Cascade Synthesis of 1,2,4-Thiadiazoles from β-Ketothioamides and Alkyl/Aryl Cyanides under TBN Enabling Conditions at Room Temperature
Singh, M. S., Singh, S., Shukla, G., & Ray, S. (2023) · Synthesis · doi:10.1055/a-2013-5801 · Cited by 8
Protein Glycosylation and Gut Microbiota Utilization Can Limit the In Vitro and In Vivo Metabolic Cellular Incorporation of Neu5Gc
Lin, X., Yao, H., Guo, J., Huang, Y., Wang, W., Yin, B., Li, X., Wang, T., Li, C., Xu, X., et al. (2021) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202100615 · Cited by 8
Meats, Protein and Cancer
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Nitrosyl-Heme and Heme Iron Intake from Processed Meats in Subjects from the EPIC-Spain Cohort
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Background
Fecal Biomarkers for Research on Dietary and Lifestyle Risk Factors in Colorectal Cancer Etiology
Kato, I., Startup, J. J., & Ram, J. L. (2013) · Current Colorectal Cancer Reports · doi:10.1007/s11888-013-0195-0 · Cited by 5
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BackgroundInfluential
Daily berry consumption attenuates β-catenin signalling and genotoxicity in colon carcinoma cells exposed to faecal water from healthy volunteers in a clinical trial
Slabá, H., Määttänen, M., Marttinen, M., Lapinkero, V., Päivärinta, E., & Pajari, A. (2023) · Journal of Functional Foods · doi:10.1016/j.jff.2023.105440 · Cited by 5
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Investigation of Escherichia coli O157:H7 Survival and Interaction with Meal Components during Gastrointestinal Digestion
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Authors: Kuhnle, G. G. C., Story, G. W., Reda, T., Mani, A. R., Moore, K. P., Lunn, J. C., & Bingham, S. A.
Affiliations: MRC Mitochondrial Biology Unit (GB)
The Royal Free Hospital (GB)
Corresponding author: Bingham, Sheila A.
ORCID: Kuhnle, Gunter G.C.
Story, Giles W.
Mani, Ali R.
Venue: Free Radical Biology and Medicine
Publisher: Elsevier BV
Published: 2007-10
Volume: 43
Issue: 7
Pages: 1040-1047
ISSN: 0891-5849 (ISSN-L)
DOI: 10.1016/j.freeradbiomed.2007.03.011
OpenAlex: W2079577516
Cited by: 146
References: 59
Citations by year: 2026: 5 · 2025: 4 · 2024: 27 · 2023: 7 · 2022: 6 · 2021: 5 · 2020: 6 · 2019: 10 · 2018: 7 · 2017: 7 · 2016: 4 · 2015: 9 · 2014: 7 · 2013: 7 · 2012: 4
FWCI: 10.10
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Free Radical Biology and Medicine (publishedVersion)
PubMed (publishedVersion)
UCL Discovery (University College London) (submittedVersion)
Funders: Food Standards Agency
Medical Research Council
Topics: Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Meat and Animal Product Quality
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
Keywords: nitroso compounds, endogenous nitrosation, red meat, processed meat, heme, S-nitrosothiols, colorectal cancer, DNA adducts, simulated gastric conditions, hemoglobin, vegetarian diet, gastrointestinal tract
MeSH terms: Apoproteins, Diet, Electron Spin Resonance Spectroscopy, Feces, Gastric Mucosa, Heme, Hemoglobins, Humans, Ileum, Iron, Kinetics, Meat, Nitroso Compounds, Serum Albumin, Bovine, Diet, Vegetarian, S-Nitrosothiols, Gastrointestinal Tract

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Diet-induced endogenous formation of nitroso compounds in the GI tract

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