The western diet, endogenous cytotoxin and genotoxin formation, a possible cause of carcinogenesis
Bibliographic record
Abstract
AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 3098 The risk of colorectal and other epithelial cancers is associated with excessive energy consumption and increased oxidative stress, typical for individuals consuming any Western diet high in sugars, fats and meats, low in vegetables and micronutrients. Here we have shown that two factors oxidative stress and fructose together caused marked cytotoxicity towards isolated hepatocytes. During inflammation, hepatic macrophages (Kupffer cells) release cytokines and NADPH oxidase becomes activated releasing reactive oxygen species. Our hepatocyte inflammation model involves exposing hepatocytes to a H2O2 generating system at a low rate that does not affect cell viability or glutathione levels. Hepatocyte viability was also not affected by high concentrations of fructose. Fructose cytotoxicity in the presence of a H2O2 generating system was preceded by increased ROS generation, disrupted mitochondrial membrane potential (MMP), and depleted ATP levels. Interestingly, such cytotoxicity, ROS generation, and MMP disruption was significantly ameliorated by the iron chelator: desferoxamine, as well as micronutrients: ascorbic acid, pyridoxal, carnitine, and thiamine. The cytoprotection specificity of these agents was unlike that seen with cytotoxicity induced by high H2O2 concentrations alone. Fructose cytotoxicity was further increased by added iron or by depleting glutathione beforehand. Glyceraldehyde and dihydroxyacetone metabolites of fructose were several fold more cytotoxic than fructose and markedly increased cellular ROS and lipid peroxidation. Overall, the order of hepatocyte cytotoxicity found for sugar/metabolites was dihydroxyacetone > glyceraldehyde > fructose > xylitol, sorbitol > glycerol, deoxyribose, glucose > ribose. Addition of H2O2 to glyceraldehyde or dihydroxyacetone in a cell free system also caused rapid oxygen uptake and further H2O2 formation that was attributed to autoxidation. Furthermore added linoleic acid or DNA was also cooxidised to form thiobarbituric acid reactive products and 8-oxodG respectively thereby implicating carbon radicals and ROS respectively. We hypothesize that ROS formed by plasma membrane NADPH oxidase during inflammation oxidises the fructose metabolites glyceraldehyde and dihydroxyacetone to ROS and carbon radicals. These reactive species cause lipid peroxidation and DNA oxidation that contribute to cytotoxicity and carcinogenesis. The cytotoxic and genotoxic mechanism described could also explain the association of other common chronic diseases of the developed and developing world with the Western diet including non-alcoholic steatohepatitis, Type 2 diabetes, hypertension, cardiovascular disease, rheumatoid arthritis or the association of colorectal cancer risk with hyperinsulinemia and the metabolic syndrome.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.024 | 0.008 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".