Toxicidad celular provocada por el Hierro Hemínico (Hemoglobina y Mioglobina)

El hierro está siendo ubicado como un factor independiente de genotoxicidad, la cual está asociada a ciertas proliferaciones neoplasicas (cánceres, tumores benignos), como también en enfermedades neurodegenerativas, diabetes, e incluso en daños de las arterias como la ateriosclerosis (arteriosclerosis por acumulación de lípidos - principalmente, colesterol- y macrofagos en la íntima) .

Ya hace muchos años que se lo comenzó a considerar como tal. Y ahora, con el transcurso de las investigaciones, se comienza ver claramente lo potencialmente peligroso que es el consumo indiscriminado de alimentos con alto contenido de hierro de alta biodisponibilidad (concretamente, hierro hemínico, de la hemoglobina y de la mioglobina, presente en las carnes).

En este estudio, hoy confirmado por muchos otros estudios, se planteaba los riesgos que implica la capacidad oxidante, inductora de radicales libres, del hierro.

Redox reactions of hemoglobin and myoglobin: biological and toxicological implications.

Alayash AI, Patel RP, Cashon RE.

Source: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.


Direct cytotoxic effects associated with hemoglobin (Hb) or myoglobin (Mb) have been ascribed to redox reactions (involving either one- or two-electron steps) between the heme group and peroxides. These interactions are the basis of the pseudoperoxidase activity of these hemoproteins and can be cytotoxic when reactive species are formed at relatively high concentrations during inflammation and typically lead to cell death. Peroxides relevant to biological systems include hydrogen peroxide, lipid hydroperoxides, and peroxynitrite. Reactions between Hb/Mb and peroxides form the ferryl oxidation state of the protein, analogous to compounds I and II formed in the catalytic cycle of many peroxidase enzymes. This higher oxidation state of the protein is a potent oxidant capable of promoting oxidative damage to most classes of biological molecules. Free iron, released from Hb, also has the potential to promote oxidative damage via classical "Fenton" chemistry. It has become increasingly evident that Hb/Mb redox reactions or their by-products play a critical role in the pathophysiology of some disease states. This review briefly discusses the reactions of Hb/Mb with biological peroxides, potential cytotoxicity and the impact of these interactions on modulation of cell signaling pathways regulated by these reactive species. Also discussed in this article is the role of heme-protein chemistry in relation to the toxicity of hemoproteins.

PMID: 11396484 [PubMed - indexed for MEDLINE]

Las siguientes investigaciones demuestran que el paradigma de la definciencia del hierro deberá ser cambiado. Hoy, se podría deducir, de todas estas investigaciones, que es mucho más peligroso su exceso que su deficiencia. Incluso, como en otras investigaciones se ha propuesto, una deficiencia marginal de hierro sería beneficioso para la salud.

Hemoglobin and hemin induce DNA damage in human colon tumor cells HT29 clone 19A and in primary human colonocytes.Glei M, Klenow S, Sauer J, Wegewitz U, Richter K, Pool-Zobel BL.
Department of Nutritional Toxicology, Institute for Nutrition, Friedrich-Schiller-University, Dornburger Str. 25, D-07743 Jena, Germany.


Epidemiological findings have indicated that red meat increases the likelihood of colorectal cancer. Aim of this study was to investigate whether hemoglobin, or its prosthetic group heme, in red meat, is a genotoxic risk factor for cancer. Human colon tumor cells (HT29 clone 19A) and primary colonocytes were incubated with hemoglobin/hemin and DNA damage was investigated using the comet assay. Cell number, membrane damage, and metabolic activity were measured as parameters of cytotoxicity in both cell types. Effects on cell growth were determined using HT29 clone 19A cells. HT29 clone 19A cells were also used to explore possible pro-oxidative effects of hydrogen peroxide (H2O2) and antigenotoxic effects of the radical scavenger dimethyl sulfoxide (DMSO). Additionally we determined in HT29 clone 19A cells intracellular iron levels after incubation with hemoglobin/hemin. We found that hemoglobin increased DNA damage in primary cells (> or =10 microM) and in HT29 clone 19A cells (> or =250 microM). Hemin was genotoxic in both cell types (500-1000 microM) with concomitant cytotoxicity, detected as membrane damage. In both cell types, hemoglobin and hemin (> or =100 microM) impaired metabolic activity. The growth of HT29 clone 19A cells was reduced by 50 microM hemoglobin and 10 microM hemin, indicating cytotoxicity at genotoxic concentrations. Hemoglobin or hemin did not enhance the genotoxic activity of H2O2 in HT29 clone 19A cells. On the contrary, DMSO reduced the genotoxicity of hemoglobin, which indicated that free radicals were scavenged by DMSO. Intracellular iron increased in hemoglobin/hemin treated HT29 clone 19A cells, reflecting a 40-50% iron uptake for each compound. In conclusion, our studies show that hemoglobin is genotoxic in human colon cells, and that this is associated with free radical mechanisms and with cytotoxicity, especially for hemin. Thus, hemoglobin/hemin, whether available from red meat or from bowel bleeding, may pose genotoxic and cytotoxic risks to human colon cells, both of which contribute to initiation and progression of colorectal carcinogenesis.

PMID: 16226281  [PubMed - indexed for MEDLINE]

Heme iron from meat and risk of colorectal cancer: a meta-analysis and a review of the mechanisms involved.

Bastide NM, Pierre FH, Corpet DE.
Source: INRA TOXALIM (Research Centre in Food Toxicology), Université de Toulouse; INP ENVT, Toulouse, France.

Red meat and processed meat intake is associated with a risk of colorectal cancer, a major cause of death in affluent countries. Epidemiological and experimental evidence supports the hypothesis that heme iron present in meat promotes colorectal cancer. This meta-analysis of prospective cohort studies of colon cancer reporting heme intake included 566,607 individuals and 4,734 cases of colon cancer. The relative risk of colon cancer was 1.18 (95% CI: 1.06-1.32) for subjects in the highest category of heme iron intake compared with those in the lowest category. Epidemiological data thus show a suggestive association between dietary heme and risk of colon cancer. The analysis of experimental studies in rats with chemically-induced colon cancer showed that dietary hemoglobin and red meat consistently promote aberrant crypt foci, a putative precancer lesion. The mechanism is not known, but heme iron has a catalytic effect on (i) the endogenous formation of carcinogenic N-nitroso compounds and (ii) the formation of cytotoxic and genotoxic aldehydes by lipoperoxidation. A review of evidence supporting these hypotheses suggests that both pathways are involved in heme iron toxicity.

©2011 AACR. PMID:21209396 [PubMed - indexed for MEDLINE]

Lipid peroxyl radicals from oxidized oils and heme-iron: implication of a high-fat diet in colon carcinogenesis.

Sawa T, Akaike T, Kida K, Fukushima Y, Takagi K, Maeda H.
Source: Department of Microbiology, Kumamoto University School of Medicine, Japan.
A diet high in fat and iron is known as a risk factor in cancer epidemiology. However, the details of the molecular mechanism remains to be elucidated. We examined the possible implication of lipid peroxyl radicals generated from fatty acids and heme-iron in DNA damage, and hence in the possibility of colon cancer. F344 female rats were given N-nitroso-N-methylurea six times during a 2-week period and then fed diets containing different amounts of safflower oil and hemoglobin (rich in iron) for 36 weeks; the occurrence of colon cancer was determined by H&E staining. In this animal model, simultaneous feeding of a fat diet and heme-iron produced a significant increase (P < 0.05) in the incidence of colon cancer compared with a diet without hemoglobin. Electron paramagnetic resonance and chemiluminescence studies revealed that oxidized refined vegetable oils, particularly safflower oil, readily generated lipid peroxyl radicals in the presence of various heme compounds, and the peroxyl radicals did effectively cleave DNA. Unpurified native vegetable oils contain a high amount of peroxyl radical scavengers, whereas conventional refining processes seem to reduce the levels of many valuable anti-peroxyl radical compounds abundant in plant seeds. In conclusion, lipid peroxides and heme components generate peroxyl radical species that exert DNA-cleaving activity. A plausible explanation is that lipid peroxyl radicals thus generated, which originated from routine dietary components such as fat and red meat, may contribute, at least in part, to the high incidence of colon cancer.
PMID: 9829709 [PubMed - indexed for MEDLINE]

Red Meat and Colon Cancer
The Cytotoxic and Hyperproliferative Effects of Dietary Heme

Aloys L. A. Sesink2, Denise S. M. L. Termont, Jan H. Kleibeuker, and Roelof Van der Meer+ Author Affiliations

Wageningen Centre for Food Sciences, Netherlands Institute for Dairy Research Food Research, Section Nutrition and Health, 6710 BA Ede, the Netherlands [A. L. A. S., D. S. M. L. T., R. V. d. M.], and Department of Gastroenterology, University Hospital, Groningen, the Netherlands [J. H. K.]


The intake of a Western diet with a high amount of red meat is associated with a high risk for colon cancer. We hypothesize that heme, the iron carrier of red meat, is involved in diet-induced colonic epithelial damage, resulting in increased epithelial proliferation. Rats were fed purified control diets, or purified diets supplemented with 1.3 μmol/g of hemin (ferriheme), protoporphyrin IX, ferric citrate, or bilirubin (n = 8/group) for 14 days. Feces were collected for biochemical analyses. Fecal cytotoxicity was determined from the degree of lysis of erythrocytes by fecal water. Colonic epithelial proliferation was measured in vivo using [3H]thymidine incorporation into colonic mucosa.
The colonic epithelial proliferation in heme-fed rats was significantly increased compared to control rats [55.2 ± 5.8 versus 32.6 ± 6.3 dpm/μg DNA (mean ± SE); P < 0.05]. The fecal water of the heme group was highly cytotoxic compared to the controls (90 ± 2% versus 2 ± 1%; P < 0.001), although the concentrations of cytotoxic bile acids and fatty acids were significantly lower. Organic iron was significantly increased compared to the controls (257 ± 26 versus 80 ± 21 μm; P < 0.001). Spectrophotometric analyses suggest that this organic iron is heme-associated. Thiobarbituric acid-reactive substances were greatly increased in the fecal water of heme-fed rats compared to the controls (177 ± 12 versus 59 ± 7 μm; P < 0.05). Heme itself could not account for the increased cytotoxicity because the addition of heme to the fecal water of the control group, which was equimolar to the organic iron content of the fecal water of the heme group, did not influence the cytotoxicity. Hence, an additional heme-induced cytotoxic factor is involved, which may be modulated by the generation of luminal-reactive oxygen species. Protoporphyrin IX, ferric citrate, and bilirubin did not increase proliferation and cytotoxicity. In conclusion, dietary heme leads to the formation of an unknown, highly cytotoxic factor in the colonic lumen. This suggests that, in heme-fed rats, colonic mucosa is damaged by the intestinal contents. This results in a compensatory hyperproliferation of the epithelium, which supposedly increases the risk for colon cancer.

©1999 American Association for Cancer Research.