title: 4-Hydroxy-2(E)-nonenal metabolism differs in Apc(+/+) cells and in Apc(Min/+) cells: it may explain colon cancer promotion by heme iron.
abstract: Animal and epidemiological studies suggest that dietary heme iron would promote colorectal cancer. Oxidative properties of heme could lead to the formation of cytotoxic and genotoxic secondary lipid oxidation products, such as 4-hydroxy-2(E)-nonenal (HNE). This compound is more cytotoxic to mouse wild-type colon cells than to isogenic cells with a mutation on the adenomatous polyposis coli (APC) gene. The latter thus have a selective advantage, possibly leading to cancer promotion. This mutation is an early and frequent event in human colorectal cancer. To explain this difference, the HNE biotransformation capacities of the two cell types have been studied using radiolabeled and stable isotope-labeled HNE. Apc-mutated cells showed better biotransformation capacities than nonmutated cells did. Thiol compound conjugation capacities were higher for mutated cells, with an important advantage for the extracellular conjugation to cysteine. Both cells types were able to reduce HNE to 4-hydroxynonanal, a biotransformation pathway that has not been reported for other intestinal cells. Mutated cells showed higher capacities to oxidize 4-hydroxynonanal into 4-hydroxynonanoic acid. The mRNA expression of different enzymes involved in HNE metabolism such as aldehyde dehydrogenase 1A1, 2 and 3A1, glutathione transferase A4-4, or cystine transporter xCT was upregulated in mutated cells compared with wild-type cells. In conclusion, this study suggests that Apc-mutated cells are more efficient than wild-type cells in metabolizing HNE into thiol conjugates and 4-hydroxynonanoic acid due to the higher expression of key biotransformation enzymes. These differential biotransformation capacities would explain the differences of susceptibility between normal and Apc-mutated cells regarding secondary lipid oxidation products.
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.forename: Isabelle
authors.initials: I
authors.lastname: Jouanin
authors.forename: Sabine
authors.initials: S
authors.lastname: Dalleau
authors.forename: Sylviane
authors.initials: S
authors.lastname: Taché
authors.forename: Mathilde
authors.initials: M
authors.lastname: Gieules
authors.forename: Laurent
authors.initials: L
authors.lastname: Debrauwer
authors.forename: Cécile
authors.initials: C
authors.lastname: Canlet
authors.forename: Laurence
authors.initials: L
authors.lastname: Huc
authors.forename: Jacques
authors.initials: J
authors.lastname: Dupuy
authors.forename: Fabrice H F
authors.initials: FH
authors.lastname: Pierre
authors.forename: Françoise
authors.initials: F
authors.lastname: Guéraud
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006418:Heme / Q000009:adverse effects / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D007501:Iron / Q000009:adverse effects / Q000378:metabolism / Q000633:toxicity*; D007553:Isotope Labeling; D013058:Mass Spectrometry; D051379:Mice; D009154:Mutation; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D000447:Aldehydes; D012333:RNA, Messenger; D006418:Heme; D007501:Iron; D000444:Aldehyde Dehydrogenase; D005982:Glutathione Transferase; D005978:Glutathione; C027576:4-hydroxy-2-nonenal