Cancer Letters

Cancer Letters

Volume 202, Issue 2, 30 December 2003, Pages 125-129
Cancer Letters

Marginal dietary thiamin deficiency induces the formation of colonic aberrant crypt foci (ACF) in rats

https://doi.org/10.1016/j.canlet.2003.08.005Get rights and content

Abstract

Thiamin deficiency leads to the endogenous formation of genotoxic α-oxoaldehydes (glyoxals). To evaluate whether marginal deficiency poses a carcinogenesis risk we fed rats AIN-76A sucrose-based diets containing thiamin at 4.9 (control), 1.6 or 1.0 mg/kg diet and examined their colons after 160 days. Reduced thiamin increased aberrant crypt foci (ACF) from 1.14±0.46 to 3.70±1.17 and 2.60±1.02 ACF/colon in the absence of exogenous carcinogen or of symptoms of beriberi. Since typical Western diets can provide marginal levels of thiamin with high levels of simple sugars, individuals could be exposed to an increased risk of colon and perhaps other cancers.

Introduction

Diets deficient in thiamin as seen in the case of beriberi have been associated with the presence of methylglyoxal in body fluids [1], [2], [3], [4]. Although the analytical techniques used were of questionable accuracy and precision, it now appears likely that the elevated levels of methylglyoxal, and of related glyoxal and 3-deoxyglucosone, could have been a result of decreased activity of the thiamin-dependent enzymes involved in glycolysis and an increase of reactive intermediates in carbohydrate metabolism [5]. The triose phosphates formed by normal glycolysis from glucose and fructose, for instance, are known to spontaneously rearrange their structure to form reactive α-oxoaldehydes [6] which are normally removed by glyoxylase I and II, in the presence of glutathione (GSH) [7]. However, in thiamin deficiency the activity of α-transketolase and the pyruvate dehydrogenase complex are decreased [8] and GSH concentrations depleted [9]. Such metabolic changes could lead to an increase in cytoplasmic α-oxoaldehyde levels.

We suggest that endogenously formed α-oxoaldehydes associated with thiamin deficiency may pose a cancer risk. Methylglyoxal, glyoxal and 3-deoxyglucosone are reactive compounds that can form adducts to proteins and DNA [10]. They are known to cause miscoding, point mutations and cytogenetic damage [11], [12], [13]. Although carcinogenesis studies with methylglyoxal and glyoxal have proved equivocal, these studies were made with exogenous sources of the mutagens [14]. In thiamin deficiency, α-oxoaldehydes are produced in the cytoplasm of all cells metabolizing carbohydrate, particularly when the metabolism of carbohydrate is rapid e.g. after the consumption of simple sugars.

We report here a preliminary test of this hypothesis, that diets high in simple sugars but with marginal thiamin deficiency pose a cancer risk. For this purpose we chose the sucrose-based diet with thiamin levels that were low but still known to support normal growth, since energy and weight restriction can reduce carcinogenesis [15]. We chose the formation of colonic aberrant crypt foci (ACF) in F344 rats as our measure of early carcinogenesis. This biomarker is closely associated with colon carcinogenesis in experimental studies with genotoxic, non-genotoxic carcinogens and carcinogenesis inhibitors, as well as with human colon cancer [16], [17], [18], [19], [20], though only a fraction of ACF develop into colon cancers [21].

Section snippets

Materials and methods

Thirty-four male Fischer 344 rats (Harlan Sprague–Dawley, Inc., Indianapolis, IN) each weighing approximately 110 g were housed in pairs in plastic cages with 12 h light/dark cycle, 22 °C temperature and 50% humidity. Care and treatment of the rats were in compliance with the guidelines of the Canadian Council on Animal Care, and the protocol was approved by the University of Toronto Animal Care Committee. The animals were acclimatized for 7 days on rodent chow (Purina 5001, Ralston Purina

Results

The reduced levels of dietary thiamin had metabolic effects. The initial weights of the three groups of animals were the same, but by 42 days the weights of the animals with the lowest level of thiamin fell below the other two groups reaching a difference of 9% at 160 days (Table 1). This was apparently not a consequence of reduced food consumption, as food consumption by the animals on low thiamin was similar to the controls. The intermediate thiamin group had a significant, paradoxically

Discussion

We have found that rats fed with marginally deficient thiamin diet (1.6 mg/kg) do not have a decreased weight gain or overt evidence of beriberi, but have decreased plasma thiamin and RBC transketolase levels and an increased number of ACF, observed in the colon after a period of 160 days. The results are consistent with our expectations that thiamin deficiency may increase risk of carcinogenesis, but they raise several unexpected questions.

First, how could reduced thiamin lead to increased

Acknowledgements

We thank Salomon Minkin for advice on statistics, Saul Rabinovich for helpful discussions and Amanda Hanna and Tracy Hartman for technical assistance. Supported by the Cancer Research Society and the Cancer Research Institute of the Canadian Institutes for Health Research.

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