1-(1-glycero)dodeca-1-3-5-7-9-pentaene and Colorectal-Neoplasms

Colorectal cancer is one of the most common internal malignancies in Western society. The cause of this disease appears to be multifactorial and involves genetic as well as environmental aspects. The human colon is continuously exposed to a complex mixture of compounds, which is either of direct dietary origin or the result of digestive, microbial and excretory processes. In order to establish the mutagenic burden of the colorectal mucosa, analysis of specific compounds in feces is usually preferred. Alternatively, the mutagenic potency of fecal extracts has been determined, but the interpretation of these more integrative measurements is hampered by methodological shortcomings. In this review, we focus on exposure of the large bowel to five different classes of fecal mutagens that have previously been related to colorectal cancer risk. These include heterocyclic aromatic amines (HCA) and polycyclic aromatic hydrocarbons (PAH), two exogenous factors that are predominantly ingested as pyrolysis products present in food and (partially) excreted in the feces. Additionally, we discuss N-nitroso-compounds, fecapentaenes and bile acids, all fecal constituents (mainly) of endogenous origin. The mutagenic and carcinogenic potency of the above mentioned compounds as well as their presence in feces, proposed mode of action and potential role in the initiation and promotion of human colorectal cancer are discussed. The combined results from in vitro and in vivo research unequivocally demonstrate that these classes of compounds comprise potent mutagens that induce many different forms of genetic damage and that particularly bile acids and fecapentaenes may also affect the carcinogenic process by epigenetic mechanisms. Large inter-individual differences in levels of exposures have been reported, including those in a range where considerable genetic damage can be expected based on evidence from animal studies. Particularly, however, exposure profiles of PAH and N-nitroso compounds (NOC) have to be more accurately established to come to a risk evaluation. Moreover, lack of human studies and inconsistency between epidemiological data make it impossible to describe colorectal cancer risk as a result of specific exposures in quantitative terms, or even to indicate the relative importance of the mutagens discussed. Particularly, the polymorphisms of genes involved in the metabolism of heterocyclic amines are important determinants of carcinogenic risk. However, the present

Topics: Amines; Bile Acids and Salts; Colorectal Neoplasms; Cooking; Feces; Heterocyclic Compounds; Humans; Mutagenesis; Mutagens; Nitroso Compounds; Polycyclic Aromatic Hydrocarbons; Polyenes; Risk Factors

The free water phase of feces (fecal water) may mediate the effects of diet on colon carcinogenesis. We examined the effects of fecal water from adenoma patients and controls on three parameters in colonocytes believed to be relevant to tumorigenesis, i.e. genotoxicity in intact cells and on isolated DNA, proliferative activity and activator protein-1 (AP-1) activity.. Genotoxicity in intact colonic cells was assayed using the single-cell gel electrophoresis assay ('comet' assay) and on isolated DNA using double-stranded DNA from the X-174 RF plasmid. Cell proliferation was assessed using the commercially available 'alamar blue' proliferation kit and AP-1 activity using cells transiently transfected with an AP-1-luciferase reporter construct.. The data showed that lipid extracts of fecal water samples from the adenoma patients had a significantly higher capacity to induce cell proliferation than those from controls, and that this effect could be explained to a large extent by the concentrations of deoxycholic and chenodeoxycholic acids in the fecal water using regression models. No difference between patients and controls was observed for induction of AP-1 activity or induction of DNA strand breaks in intact cells. However, induction of DNA strand breaks in isolated DNA was significantly higher for the fecal waters from patients than for those from controls, which could be explained in part in a regression model by concentrations of lithocholic acid in fecal water and fecapentaene-12 in feces.. Our results support the hypothesis that the biochemistry of fecal waters from adenoma patients and controls differs.

Topics: Adenoma; Adult; Body Water; Cell Division; Cholic Acids; Colorectal Neoplasms; DNA Damage; Feces; Female; Humans; Male; Middle Aged; Polyenes; Transcription Factor AP-1

The fecapentaenes are potent mutagens found in high concentrations in the stools of some individuals. These compounds are produced in vivo by common species of the colonic microflora, from precursors of unknown origin. The fecapentaenes have been postulated to increase the risk of colorectal cancer. To test this hypothesis, we measured fecapentaene excretion in 69 patients with adenocarcinoma of the colon or rectum, newly diagnosed at three Washington, DC area hospitals. The cases were compared with 114 surgical controls, frequency matched to the cases on age, sex, and hospital. We attempted to measure fecapentaene excretion 4 times for each subject: before surgery; and at 1 mo; 3 mo; and 6 mo following surgery. Contrary to our study hypothesis, we found fecapentaene excretion during the four study periods to be similar or even lower in cases compared to controls. An indirect measurement of fecapentaene precursors also tended to be lower in cases. The case-control differences could not be explained as effects of bleeding or of the colorectal diagnostic workup, which was assessed in a separate group of 86 patients. We conclude from these data that the excretion of fecapentaenes does not increase the risk of colorectal cancer, at least when measured near the time of diagnosis.

Topics: Aged; Colorectal Neoplasms; Feces; Female; Humans; Male; Middle Aged; Mutagens; Polyenes