Mucosa-specific DNA adducts in human small intestine: a comparison with the colon

Hamada, Kazuhisa; Umemoto, Atsushi; Kajikawa, Aiichiro; Tanaka, Masaki; Seraj, Mohammed Jabed; Nakayama, Masahiro; Kubota, Akio; Monden, Yasumasa

doi:10.1093/carcin/15.11.2677

Cited by 17 publications

(3 citation statements)

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“…The connection between declining serum cholesterol concentrations and colon cancer [ 25 , 26 , 27 ] may involve several factors. First, epithelial cell mutations occur during colonic tumorigenesis cause a decrease in intestinal cholesterol uptake [ 24 , 28 ]. Second, to meet the increasing demand for cell proliferation, cancer cells significantly enhance cholesterol absorption and synthesis [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Azoxymethane Alters the Plasma Metabolome to a Greater Extent in Mice Fed a High-Fat Diet Compared to an AIN-93 Diet

et al. 2021

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Consumption of a high-fat diet (HFD) links obesity to colon cancer in humans. Our data show that a HFD (45% energy fat versus 16% energy fat in an AIN-93 diet (AIN)) promotes azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation in a mouse cancer model. However, the underlying metabolic basis remains to be determined. In the present study, we hypothesize that AOM treatment results in different plasma metabolomic responses in diet-induced obese mice. An untargeted metabolomic analysis was performed on the plasma samples by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We found that 53 of 144 identified metabolites were different between the 4 groups of mice (AIN, AIN + AOM, HFD, HFD + AOM), and sparse partial least-squares discriminant analysis showed a separation between the HFD and HFD + AOM groups but not the AIN and AIN + AOM groups. Moreover, the concentrations of dihydrocholesterol and cholesterol were inversely associated with AOM-induced colonic ACF formation. Functional pathway analyses indicated that diets and AOM-induced colonic ACF modulated five metabolic pathways. Collectively, in addition to differential plasma metabolomic responses, AOM treatment decreases dihydrocholesterol and cholesterol levels and alters the composition of plasma metabolome to a greater extent in mice fed a HFD compared to the AIN.

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Section: Discussionmentioning

confidence: 99%

Azoxymethane Alters the Plasma Metabolome to a Greater Extent in Mice Fed a High-Fat Diet Compared to an AIN-93 Diet

et al. 2021

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“…There are a few probable causes. For example, during the AOM-induced ACF formation, epithelial cell mutations may cause a decrease in a certain nutrient (e.g., cholesterol) uptake [ 20 , 21 ]. Additionally, as there was a weight loss in the AIN + AOM and HFD + AOM groups in our previous data [ 8 ], and an intestinal cachexia may occur because of metabolic and nutritional changes during the progression of tumorigenesis [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Changes in the Fecal Metabolome Accompany an Increase in Aberrant Crypt Foci in the Colon of C57BL/6 Mice Fed with a High-Fat Diet

et al. 2022

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High-fat diet (HFD)-induced obesity is a risk factor for colon cancer. Our previous data show that compared to an AIN-93 diet (AIN), a HFD promotes azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation and microbial dysbiosis in C57BL/6 mice. To explore the underlying metabolic basis, we hypothesize that AOM treatment triggers a different fecal metabolomic profile in C57BL/6 mice fed the HFD or the AIN. We found that 65 of 196 identified metabolites were significantly different among the four groups of mice (AIN, AIN + AOM, HFD, and HFD + AOM). A sparse partial least squares discriminant analysis (sPLSDA) showed that concentrations of nine fecal lipid metabolites were increased in the HFD + AOM compared to the HFD, which played a key role in overall metabolome group separation. These nine fecal lipid metabolite concentrations were positively associated with the number of colonic ACF, the cell proliferation of Ki67 proteins, and the abundance of dysbiotic bacteria. These data suggest that the process of AOM-induced ACF formation may increase selective fecal lipid concentrations in mice fed with a HFD but not an AIN. Collectively, the accumulation of these critical fecal lipid species may alter the overall metabolome during tumorigenesis in the colon.

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“…It is based on the hypothesis that tissues with low or reduced levels of GSTs may have a low or reduced capacity to detoxify carcinogens, resulting in more cytogenetic damage, which in turn can lead to a higher tumour risk (9)(10)(11)(12)(13)(14)(15)(16). The rst line of evidence is found in genetic epidemiology.…”

Section: Protective Role Of Gsts In Carcinogenesismentioning

confidence: 99%

The Glutathione Biotransformation System and Colorectal Cancer Risk in Humans

Grubben

Nagengast

Katan

et al. 2001

Scandinavian Journal of Gastroenterology

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Grubben MJAL, Nagengast FM, Katan MB, Peters WHM. The glutathione biotransformation system and colorectal cancer risk in humans. Scand J Gastroenterol 2001;36 Suppl 234:68-76. Evidence for a protective role of the glutathione biotransformation system in carcinogenesis is growing. However, most data on this system in relation to colorectal cancer originate from animal studies. Here we review the human data. In humans, a signi cant association was found between glutathione S-transferase (GST) activity in the mucosa along the gastrointestinal tract and the corresponding tumour incidence. Low activity was correlated with high tumour incidence and vice versa. Also, in normal colonic mucosa, GST activity is lower in patients at risk of colon cancer than in healthy controls and therefore interventions which increase the glutathione detoxi cation capacity may reduce cancer incidence. Consumption of vegetables and fruit is associated with a lower risk of colorectal cancer. Human intervention studies showed that (components from) vegetables induced colonic glutathione detoxi cation capacity. Such an effect could contribute to a lower colon cancer risk, but further data are needed. The human GSTs consist of four main classes-alpha (A), mu (M), pi (P) and theta (T)-each of which is divided into one or more isoforms. Functional polymorphisms are known for the GST genes M1, P1 and T1 and they all lead to less active enzymes compared to the wild-type gene products. However, studies that compared these GST polymorphisms in relation to colon cancer risk were not conclusive with respect to an increased or decreased risk of a particular genotype. Diet or medication can also in uence the expression levels of speci c isoenzymes and the effect of such interventions on cancer risk deserves more attention.

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Mucosa-specific DNA adducts in human small intestine: a comparison with the colon

Cited by 17 publications

References 0 publications

Azoxymethane Alters the Plasma Metabolome to a Greater Extent in Mice Fed a High-Fat Diet Compared to an AIN-93 Diet

Azoxymethane Alters the Plasma Metabolome to a Greater Extent in Mice Fed a High-Fat Diet Compared to an AIN-93 Diet

Changes in the Fecal Metabolome Accompany an Increase in Aberrant Crypt Foci in the Colon of C57BL/6 Mice Fed with a High-Fat Diet

The Glutathione Biotransformation System and Colorectal Cancer Risk in Humans

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