Heme-Iron-Induced Production of 4-Hydroxynonenal in Intestinal Lumen May Have Extra-Intestinal Consequences through Protein-Adduct Formation.

Julia Keller,Sylvie Chevolleau,Maria-Helena Noguer-Meireles,Vassilia Theodorou,Françoise Guéraud,Fabrice Pierre,Mylène Delosière,Denys Durand,Estelle Pujos-Guillot,Charlotte Joly,Florence Blas-Y-Estrada,Isabelle Jouanin,Céline Chantelauze,Laurent Debrauwer

doi:10.3390/antiox9121293

Abstract

Some epidemiological studies show that heme iron consumption, in red meat, is associated to the development of several chronic diseases, including cancers and cardio-metabolic diseases. As heme iron intestinal absorption is finely regulated, we hypothesized that heme iron may act indirectly, through the peroxidation of dietary lipids, in food or in the intestinal lumen during digestion. This heme-iron-induced lipid peroxidation provokes the generation of toxic lipid oxidation products that could be absorbed, such as 4-hydroxynonenal (HNE). In a first experiment, heme iron given to rats by oral gavage together with the linoleic-acid-rich safflower oil induced the formation of HNE in the intestinal lumen. The HNE major urinary metabolite was elevated in the urine of the treated rats, indicating that this compound has been absorbed. In a second experiment, we showed that stable isotope-labeled HNE given orally to rats was able to reach non-intestinal tissues as a bioactive form and to make protein-adducts in heart, liver and skeletal muscle tissues. The presence of HNE-protein adducts in those tissues suggests a putative biological role of diet-originating HNE in extra-intestinal organs. This finding could have major consequences on the onset/development of chronic diseases associated with red meat over-consumption, and more largely to peroxidation-prone food consumption.

Highlights

Epidemiological studies show that excessive red meat consumption has been associated to the onset/progression of several chronic diseases, conclusively for colorectal cancer and in extra intestinal localizations for other cancers, in a less obvious way [1]
We have previously shown that dietary heme iron, but not ferric citrate given as the same iron molar concentration, could induce a cancer-promoting environment in the colon, through the luminal over-generation of cyto- and geno-toxic alkenals, among which 4-hydroxynonenal (HNE) seems to be the most important [8]
Protein-adducted HNE was found in feces too, with amounts matching those of free HNE (Figure 2B), and in the same order of magnitude (10–20 μg/excreted feces/sampling period 1 to 8 h post gavage, for hemin treated rats vs. less than 2 μg for rats given only safflower oil)

Summary

Introduction

Epidemiological studies show that excessive red (but not white) meat consumption has been associated to the onset/progression of several chronic diseases, conclusively for colorectal cancer and in extra intestinal localizations for other cancers (pancreas, bladder, breast, lung), in a less obvious way [1]. Some authors reported the formation of HNE following heme-induced lipid peroxidation of oil-in-water emulsion, under in vitro gastric digestion conditions [9] Those lipid peroxidation products may be the second messengers of intestinal heme iron/red meat toxicity. HNE-protein adducts of endogenous origin, i.e., formed upon cellular lipid peroxidation/oxidative stress, have been extensively studied in the literature [15] Those compounds are involved in the pathogenesis of numerous chronic diseases linked to inflammation processes [16,17]. To the best of our knowledge, this is the first report of extra-intestinal HNE-protein adducts formed upon oral administration This finding could have major consequences on the onset/development of chronic diseases associated with red/processed meat over-consumption, and more largely to peroxidation-prone food consumption

Materials and Methods

Animals

Assays

Statistical Analyses

Results and Discussion