An investigation of the endogenous formation of apparent total N-nitroso compounds in conventional microflora and germ-free rats

Massey, Robert C.; Key, Pauline; Mallett, A.K.; Rowland, Ian

doi:10.1016/0278-6915(88)90230-x

Cited by 68 publications

(36 citation statements)

References 35 publications

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“…This alkylation frequency is comparable to those found in other populations (and tissues) where there is a high cancer risk [21]. As the samples for the study presented here and for our previous work [13] were collected over a period of 5-10 yr, it seems that this population has been exposed chronically to methylating agents, possibly as a result of nitrosation reactions mediated by bacteria within the colon [22,23] or by macrophages within chronically inflamed tissue [24] or reactions that may arise from nitrosated bile acids [25]. A similar chronic exposure to methylating agents was observed in the Nile Delta region of Egypt, where individuals with schistosomiasis (which is endemic to that region) excrete high concentrations of urinaryhrnitroso compounds [26] and exhibit a high frequency of DNA alkylation in bladder DNA [20].…”

Section: Discussionsupporting

confidence: 66%

Frequency of Ki-ras mutations and DNA alkylation in colorectal tissue from individuals living in Manchester

et al. 1996

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Most human colorectal cancers arise through the accumulation of a series of genetic alterations such as point mutations within the Ki-ras and p53 genes, but the chemical carcinogens that may be implicated in these events are still unidentified. In a previous study, we showed that DNA from human colorectal tissue contained O6-methyldeoxyguanosine (O6-MedG), a promutagenic lesion arising from exposure to as yet unidentified methylating agents. To address whether such exposure may result in oncogene activation in human colorectal tumors, we examined another series of paired normal and tumor DNA samples from the lower intestinal tract for the presence of O6-MedG in DNA (as a marker of exposure) and for mutations within the Ki-ras gene. After isolation by high pressure liquid chromatography, O6-MedG was quantified by a radioimmunoassay with a limit of detection of 0.01 mumol O6-MedG/mol dG. The frequencies of methylation were 33%, 52%, and 48% for normal DNA and 58%, 32%, and 63% for tumor DNA isolated from the cecum, sigmoid colon, and rectum, respectively. Overall, 35% of the individuals had no detectable O6-MedG in the DNA from both their tumor and normal tissue. Ki-ras mutations were initially identified by a restriction site mutation assay and then sequenced to ascertain the mutations thus detected. The frequencies of mutations in tumor DNA isolated from the cecum, sigmoid colon, and rectum were 28%, 29%, and 42%, respectively. DNA isolated from macroscopically normal tissue was found to contain Ki-ras mutations in 14% of sigmoid colon samples and 12% of rectal samples. Most base mutations were in codon 12 (72%), and 64% were GC-->AT transitions: 28% and 8% were GC-->TA and CG-->CG transversions, respectively. All mutations were at the second base of either codon 12 or codon 13 except for a single GC-->TA transversion at the first base of codon 13 in a rectal tumor sample. There was no association between the presence of O6-MedG in DNA from either normal or tumor tissue or both normal and tumor tissue and the incidence of Ki-ras mutations or GC-->AT transitions in mutated Ki-ras genes. It remains to be determined, however, whether there is a relationship between methylating-agent exposure and Ki-ras mutations, as (i) the presence of O6-MedG in colorectal DNA in these samples may not represent the exposure when Ki-ras mutational activation was occurring (i.e., at some unknown time in the past), (ii) interindividual differences in repair-enzyme activity may alter susceptibility to a mutational event after exposure, (iii) the predominant mutagen in the colon and rectum may not be a methylating agent (e.g., nitric oxide), and (iv) exposure to methylating agents need not result in oncogene activation in human tissues but may perhaps promote the emergence of the mutator phenotype.

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Section: Discussionsupporting

confidence: 66%

Frequency of Ki-ras mutations and DNA alkylation in colorectal tissue from individuals living in Manchester

et al. 1996

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“…Considering the neutral pH of the bowel, the bacteria mediated NOC formation is most likely. The involvement of the colonic flora in the NOC formation was supported by the observation that in germ free rats, nitrate did not stimulate endogenous NOC formation (Massey et al, 1988). However, little is known regarding the bacterial species involved in endogenous nitrosation and different bacterial enzymes responsible for the nitrosation reaction have been described.…”

Section: Endogenous Production Of Nocsmentioning

confidence: 97%

Mechanisms Linking Colorectal Cancer to the Consumption of (Processed) Red Meat: A Review

Demeyer

Mertens

Smet

et al. 2015

Critical Reviews in Food Science and Nutrition

150

103

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Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world. The vast majority of CRC cases have been linked to environmental causes rather than to heritable genetic changes. Over the last decades, epidemiological evidence linking the consumption of red and, more convincingly, of processed red meat to CRC has accumulated. In parallel, hypotheses on carcinogenic mechanisms underlying an association between CRC and the intake of red and processed red meat have been proposed and investigated in biological studies. The hypotheses that have received most attention until now include (1) the presence of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, two groups of compounds recognized as carcinogenic, (2) the enhancing effect of (nitrosyl)heme on the formation of carcinogenic N-nitroso compounds and lipid peroxidation. However, none of these hypotheses completely explains the link between red and processed red meat intake and the CRC risk. Consequently, scientists have proposed additional mechanisms or refined their hypotheses. This review first briefly summarizes the development of CRC followed by an indepth overview and critical discussion of the different potential carcinogenic mechanisms underlying the increased CRC risk associated with the consumption of red and processed red meat.

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“…In the 1980s it was found that faecal samples contain negligible amounts of volatile NOC (Archer et al 1981), but since then newer methods to measure total NOC by chemiluminescence have been developed, and the presence of NOC in faeces in animals and man is now well established (Massey et al 1988;Rowland et al 1991;Bingham et al 1996;Silvester et al 1997;Hughes et al 1999).…”

Section: Meat and Nitrogen Metabolism In The Colonmentioning

confidence: 99%

High-meat diets and cancer risk

Bingham

1999

Proc. Nutr. Soc.

117

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Up to 80 % of breast, bowel and prostate cancers are attributed to dietary practices, and international comparisons show strong positive associations with meat consumption. Estimates of relative risk obtained from cohort investigations are in the same direction, although generally weak, and red and processed meats rather than white meat seem to be associated with elevated risk of colon cancer. In breast cancer, there are consistent associations with total meat intake and there is evidence of a dose response. Despite these associations with meat, existing studies suggest that vegetarians do not have reduced risk of breast, bowel or prostate cancer, but there are no quantitative estimates of amounts of meat consumed by meat eaters in these cohort studies. Possible mechanisms underlying epidemiological associations include the formation of heterocyclic amines in meat when it is cooked. These heterocyclic amines require acetylation by P450 enzymes, and individuals with the fast-acetylating genotype who eat high amounts of meat may be at increased risk of large-bowel cancer. NH 3 and N-nitroso compounds (NOC) formed from residues by bacteria in the large bowel are probably also important. NH 3 is a promotor of large-bowel tumours chemically induced by NOC, and some of the chromosomal mutations found in human colo-rectal cancer are consistent with effects of NOC and heterocyclic amines. However, the type, amount, and cooking method of meat or protein associated with increased risk are not certain. The effects of high levels of meat on NH 3 and NOC output are not reduced by increasing the amount of fermentable carbohydrate in the diet, but interaction between meat, NSP and vegetable intakes on the risk of cancer has not been studied comprehensively. The interaction between dietary low-penetrance genetic polymorphic and somatic mutation factors has also been investigated to a limited extent. Current Department of Health (1998) recommendations are that meat consumption should not rise, and that consumers at the top end of the distribution should consider a reduction in intakes.

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An investigation of the endogenous formation of apparent total N-nitroso compounds in conventional microflora and germ-free rats

Cited by 68 publications

References 35 publications

Frequency of Ki-ras mutations and DNA alkylation in colorectal tissue from individuals living in Manchester

Frequency of Ki-ras mutations and DNA alkylation in colorectal tissue from individuals living in Manchester

Mechanisms Linking Colorectal Cancer to the Consumption of (Processed) Red Meat: A Review

High-meat diets and cancer risk

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