title: A central role for heme iron in colon carcinogenesis associated with red meat intake.
abstract: Epidemiology shows that red and processed meat intake is associated with an increased risk of colorectal cancer. Heme iron, heterocyclic amines, and endogenous N-nitroso compounds (NOC) are proposed to explain this effect, but their relative contribution is unknown. Our study aimed at determining, at nutritional doses, which is the main factor involved and proposing a mechanism of cancer promotion by red meat. The relative part of heme iron (1% in diet), heterocyclic amines (PhIP + MeIQx, 50 + 25 μg/kg in diet), and NOC (induced by NaNO₂+ NaNO₂; 0.17 + 0.23 g/L of drinking water) was determined by a factorial design and preneoplastic endpoints in chemically induced rats and validated on tumors in Min mice. The molecular mechanisms (genotoxicity, cytotoxicity) were analyzed in vitro in normal and Apc-deficient cell lines and confirmed on colon mucosa. Heme iron increased the number of preneoplastic lesions, but dietary heterocyclic amines and NOC had no effect on carcinogenesis in rats. Dietary hemoglobin increased tumor load in Min mice (control diet: 67 ± 39 mm²; 2.5% hemoglobin diet: 114 ± 47 mm², P = 0.004). In vitro, fecal water from rats given hemoglobin was rich in aldehydes and was cytotoxic to normal cells, but not to premalignant cells. The aldehydes 4-hydroxynonenal and 4-hydroxyhexenal were more toxic to normal versus mutated cells and were only genotoxic to normal cells. Genotoxicity was also observed in colon mucosa of mice given hemoglobin. These results highlight the role of heme iron in the promotion of colon cancer by red meat and suggest that heme iron could initiate carcinogenesis through lipid peroxidation. .
authors.affiliation: INRA UMR1331; TOXALIM (Research Center in Food Toxicology); Université de Toulouse; ENVT; INP; UPS; TOXALIM; Toulouse, France. INSERM UMR-S1018; Gustave Roussy; Université Paris-Sud, Villejuif, France.
authors.forename: Nadia M
authors.initials: NM
authors.lastname: Bastide
authors.affiliation: INRA UMR1331; TOXALIM (Research Center in Food Toxicology); Université de Toulouse; ENVT; INP; UPS; TOXALIM; Toulouse, France. Faculty of Sciences, Department of Biology, University of Djilali Liabes, Sidi Bel Abbes, Algeria.
authors.forename: Fatima
authors.initials: F
authors.lastname: Chenni
authors.affiliation: INRA UMR1331; TOXALIM (Research Center in Food Toxicology); Université de Toulouse; ENVT; INP; UPS; TOXALIM; Toulouse, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Audebert
authors.affiliation: INRA UMR1331; TOXALIM (Research Center in Food Toxicology); Université de Toulouse; ENVT; INP; UPS; TOXALIM; Toulouse, France.
authors.forename: Raphaelle L
authors.initials: RL
authors.lastname: Santarelli
authors.affiliation: INRA UMR1331; TOXALIM (Research Center in Food Toxicology); Université de Toulouse; ENVT; INP; UPS; TOXALIM; Toulouse, France.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Taché
authors.affiliation: INRA UMR1331; TOXALIM (Research Center in Food Toxicology); Université de Toulouse; ENVT; INP; UPS; TOXALIM; Toulouse, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Naud
authors.affiliation: INRA UMR1331; TOXALIM (Research Center in Food Toxicology); Université de Toulouse; ENVT; INP; UPS; TOXALIM; Toulouse, France.
authors.forename: Maryse
authors.initials: M
authors.lastname: Baradat
authors.affiliation: INRA UMR1331; TOXALIM (Research Center in Food Toxicology); Université de Toulouse; ENVT; INP; UPS; TOXALIM; Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jouanin
authors.affiliation: INRA UMR1331; TOXALIM (Research Center in Food Toxicology); Université de Toulouse; ENVT; INP; UPS; TOXALIM; Toulouse, France.
authors.forename: Reggie
authors.initials: R
authors.lastname: Surya
authors.affiliation: Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading, United Kingdom.
authors.forename: Ditte A
authors.initials: DA
authors.lastname: Hobbs
authors.affiliation: Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading, United Kingdom.
authors.forename: Gunter G
authors.initials: GG
authors.lastname: Kuhnle
authors.affiliation: National Veterinary School of Toulouse; Histology - Pathology; Toulouse, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Raymond-Letron
authors.affiliation: INRA UMR1331; TOXALIM (Research Center in Food Toxicology); Université de Toulouse; ENVT; INP; UPS; TOXALIM; Toulouse, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Gueraud
authors.affiliation: INRA UMR1331; TOXALIM (Research Center in Food Toxicology); Université de Toulouse; ENVT; INP; UPS; TOXALIM; Toulouse, France.
authors.forename: Denis E
authors.initials: DE
authors.lastname: Corpet
authors.affiliation: INRA UMR1331; TOXALIM (Research Center in Food Toxicology); Université de Toulouse; ENVT; INP; UPS; TOXALIM; Toulouse, France. f.pierre@toulouse.inra.fr.
authors.forename: Fabrice H F
authors.initials: FH
authors.lastname: Pierre
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D008297:Male; D008460:Meat / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011916:Rats, Inbred F344; D012307:Risk Factors
chemical_list: D006418:Heme; D007501:Iron