Gamma-tocopherol attenuates moderate but not severe colitis and suppresses moderate colitis-promoted colon tumorigenesis in mice

Abstract

Inflammation can promote colon cancer. Mechanistic studies indicate that γ-tocopherol (γT), a major form of vitamin E in diets, has anti-inflammatory and anticancer properties. Here we investigated the effectiveness of γT and a mixture of tocopherols against colitis and colitis-promoted colon tumorigenesis in male BALB/c mice. γT or mixed tocopherols (at 0.1% diet) did not show any effect on colon tumorigenesis induced by azoxymethane (AOM, 10mg/kg) with three cycles of dextran sodium sulfate (DSS at 1.5–2.5%). γT failed to exhibit protection of severe colitis caused by three cycles of DSS at 2.5%. In contrast, when AOM-initiated carcinogenesis was promoted by relatively mild colitis induced by one-cycle DSS (1.5%), γT, but not mixed tocopherols, suppressed total multiplicity of macroscopic adenomas (P=0.06) and large adenomatous polyps (>2mm2, P<0.05) by 60% and 85%, respectively. γT also significantly decreased tumor multiplicity (>2mm2) induced by AOM with two cycles of 1.5% DSS even when dietary supplementation was started after AOM injection. Consistently, γT but not mixed tocopherols attenuated DSS (1.5%)-induced colon inflammation and damage as well as formation of atypical glandular hyperplasia. Mice supplemented with tocopherols had high fecal excretion of 13′-carboxychromanol, a long-chain vitamin E metabolite shown to have potent anti-inflammatory activities. Our study demonstrates that γT is able to alleviate moderate but not severe colitis and its promoted tumorigenesis, and indicates that inflammation severity should be considered in evaluating anticancer effectiveness of chemoprevention agents.

Analysis of vitamin E metabolites including carboxychromanols and sulfated derivatives using LC/MS/MS

“…Second, large amounts of unconjugated metabolites, especially 13 ′ -COOH and 13 ′ -OH, which are very low in the plasma, are detected in feces. This observation is consistent with previous reports (12)(13)(14). The high level of carboxychromanols in feces suggests that most long-chain metabolites are not transported to the circulation after being generated in the liver, but rather are excreted via the bile.…”

“…After a week of acclimatization, mice were randomly divided into control (AIN-93G diet) and ␥ T-or ␦ T-supplemented (0.1% diet) group. These mice were subjected to induction of colon tumorigenesis by azoxymethane/dextran sodium sulfate (AOM/ DSS) as previously described ( 12 ). When the study was terminated, mice were on supplemented diets for more than 150 days ( 12 ).…”

“…These mice were subjected to induction of colon tumorigenesis by azoxymethane/dextran sodium sulfate (AOM/ DSS) as previously described ( 12 ). When the study was terminated, mice were on supplemented diets for more than 150 days ( 12 ). During euthanasia, plasma and feces were collected.…”

Complexity of vitamin E metabolism

“…Zhao et al [136] reported that the LCMs are unconjugated in feces. Because of the lack of β-glucuronidase treatment, Jiang et al [187] could not distinguish between conjugated and non-conjugated metabolites in their fecal samples, which in turn could support the results from Zhao et al [136] . Wu and Croft [188] concluded that part of the total vitamin E undergoes enterohepatic circulation (estimated to be about 60% in rats) and that the remaining is likely lost via the fecal route [189] .…”

“…Feces contain the whole set of vitamin E metabolites, including precursors (TOHs and T3s) and water-soluble SCMs in humans [136] and mice [157,161,187] ; LCMs (especially 13'-COOH) are the main fecal metabolites with > 60% of total metabolites [187] . Zhao et al [136] reported that the LCMs are unconjugated in feces.…”