Structures of fecapentaenes, the mutagens of bacterial origin isolated from human feces

Gupta, Indranil; Baptista, José; Bruce, W. R.; T, C; Furrer, R.; Gingerich, J. S.; Grey, Arthur A.; Marai, L.; Yates, Peter; Křepinský, Jiří J.

doi:10.1021/bi00271a001

Cited by 92 publications

(30 citation statements)

References 17 publications

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“…Examples observed in vitro and in vivo are: hydrolysis of rutin to quercetin (a mutagenic aromatic amine), hydrolysis of cycasin to methylazoxymethanol (70), and hydrolysis of glucuronide-conjugated polycyclic hydrocarbons to their unconjugated, mutagenic forms (71). Fecapentaenes, potent mutagens synthesized by Bacteroides species, are also found in relatively high concentrations in human feces, although their relationship to cancer is unproven (72)(73)(74). Furthermore, bacteria ferment polysaccharides and glycoproteins to volatile fatty acids.…”

Section: Environmental Health Perspectivesmentioning

confidence: 99%

Bacterial infection as a cause of cancer.

Parsonnet

1995

Environ Health Perspect

159

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Bacterial infections traditionally have not been considered major causes of cancer. Recently, however, bacteria have been linked to cancer by two mechanisms: induction of chronic inflammation and production of carcinogenic bacterial metabolites. The most specific example of the inflammatory mechanism of carcinogenesis is Helicobacter pylori infection. H. pylori has been epidemiologically linked to adenocarcinoma of the distal stomach by its propensity to cause lifelong inflammation. This inflammation is in turn thought to cause cancer by inducing cell proliferation and production of mutagenic free radicals and N-nitroso compounds. H. pylori is the first bacterium to be termed a definite cause of cancer in humans by the International Agency for Research on Cancer. Mutagenic bacterial metabolites are also suspected to increase risk for cancer. This model is best exemplified in colon cancer. Bile salt metabolites increase colonic cell proliferation. Exogenous compounds such as rutin may be metabolized into mutagens by resident colonic flora. Moreover, Bacteroides species can produce fecapentaenes, potent in vitro mutagens, in relatively high concentrations. In vivo data on human carcinogenesis by bacterial metabolites, however, are inconsistent. Local bacterial infections may also predispose to nonnodal lymphomas, although the mechanisms for this are unknown. Gastric lymphomas and immunoproliferative small intestinal disease have been most strongly linked to underlying bacterial infection. Because bacterial infections can be cured with antibiotics, identification of bacterial causes of malignancy could have important implications for cancer prevention. -Environ Health Perspect 1 03(Suppl 8): 263-268 (1995)

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Section: Environmental Health Perspectivesmentioning

confidence: 99%

Bacterial infection as a cause of cancer.

Parsonnet

1995

Environ Health Perspect

159

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“…Mutagenic compounds to which colon mucosa are exposed include reactive aromatic compounds such as fecapentaenes (8), various pyrrolysis products generated during cooking (9), bile acids (10), and short-chain fatty acids (11). These toxins produce reactive molecules that may form bulky adducts to DNA, or may alter the structure of specific bases by oxidation-reduction reactions.…”

Section: Introductionmentioning

confidence: 99%

Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz.

Szarka²,

Yao³

et al. 1996

J. Clin. Invest.

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Prolonged exposure to mutagenic substances is strongly associated with an individual's risk of developing colorectal cancer. Clinical investigation of oltipraz as a chemopreventive agent is supported by its induction of the expression of detoxication enzymes in various tissues, and its protective activity against the formation of chemically induced colorectal tumors in animals. The goals of the present study were: to determine if oltipraz could induce detoxicating gene expression in human tissues; to identify effective nontoxic doses for more extensive clinical testing; and to establish a relationship between effects in the colon mucosa and those in a more readily available tissue, the peripheral mononuclear cell. 24 evaluable patients at high risk for colorectal cancer were treated in a dose-finding study with oltipraz 125, 250, 500, or 1,000 mg/m 2 as a single oral dose. Biochemical analysis of sequential blood samples and colon mucosal biopsies revealed increases in glutathione transferase activity at the 1ower dose levels. These effects were not observed at the higher doses. More pronounced changes were observed in detoxicating enzyme gene expression in both tissues at all doses. Peripheral mononuclear cell and colon mRNA content for ␥ -glutamylcysteine synthetase ( ␥ -GCS) and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and declined to baseline in the subsequent 7-10 d. The extent of induction of gene expression in colon mucosa reached a peak of 5.75-fold for ␥ -GCS, and a peak of 4.14-fold for DT-diaphorase at 250 mg/m 2 ; higher doses were not more effective. Levels of ␥ -GCS and DT-diaphorase correlated closely ( P Յ 0.001) between peripheral mononuclear cells and colon mucosa both at baseline and at peak. These findings demonstrate that the administration of minimally toxic agents at low doses may modulate the expression of detoxicating genes in the tissues of individuals at high risk for cancer. Furthermore, peripheral mononuclear cells may be used as a noninvasive surrogate endpoint biomarker for the transcriptional response of normal colon mucosa to drug administration. ( J. Clin. Invest. 1996. 98:1210-1217.)

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“…do not require mammalian enzymes for their activity) in the Ames Salmonella mutagenicity assay and induce about 5,000 mutants/pg [56,62], The availability of syn thetic FP-12 has enabled extensive toxicolog ical testing of the mutagen which has been shown to induce a wide range of genetic dam age in human and rodent cells in culture. For example, in human skin fibroblasts, low con centrations (0.6-10 pg/ml) of FP-12 caused single strand breaks in DNA, and induced gene mutations, unscheduled DNA synthesis (repair of DNA damage) and sister chroma tid exchanges [63].…”

Section: Microfloramentioning

confidence: 99%