Intestinal microflora plays a crucial role in the genotoxicity of the cooked food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)
University of Vienna, Wien, Vienna, Austria Carcinogenesis
(Impact Factor: 5.33).
11/2001; 22(10):1721-5. DOI: 10.1093/carcin/22.10.1721
We investigated the impact of the intestinal microflora on the genotoxicity of 2-amino-3-methylimidazo[4,5-f] quinoline (IQ), a mutagenic/carcinogenic heterocyclic amine commonly found in fried meats and fish. In parallel, we also examined the effect of the microflora on the protective effect of glucotropaeolin (GT), a glucosinolate contained in cruciferous vegetables, towards IQ-induced genotoxic effect. Conventional (NF), human flora associated (HFA) and germ free (GF) rats were treated either with 90 mg/kg IQ alone, 150 mg/kg GT alone or a combination of the two by gavage and DNA damage was determined in liver and colon cells using the alkaline single cell gel electrophoresis (SCGE) or comet assay. IQ caused a significant effect in both organs of all groups. However, DNA damage was most pronounced in NF animals. In colon cells, DNA migration was 6-fold more in IQ-exposed rats as compared with untreated controls. The effect measured with liver cells was similar. In comparison to NF rats, in HFA rats, tail length of the comets was 22 and 53% lower in liver and colon cells, respectively. Significantly weaker effects were seen in GF animals (66 and 75% lower damage in hepatocytes and colonocytes, respectively, than in NF animals). Pretreatment with GT led to a complete reduction of IQ-induced DNA damage regardless of the microbial status of the animals. In addition, a moderate decrease in spontaneous DNA damage was seen in animals that received GT alone. Our results show that the microflora has a strong impact on the genotoxic effects of IQ. We conclude that the alkaline SCGE assay with rats harbouring different flora opens new possibilities to investigate the role of intestinal bacteria on health risks caused by dietary carcinogens.
Available from: Alberto Martin
- "Anaerobic colonic bacteria, such as Eubacterium spp., have the capacity to convert IQ to 2-amino-3-methyl-3H- imidazo[4,5-f]quinoline-7-one (HOIQ), which is a known mutagen (Bashir et al., 1987; Carman et al., 1988). IQ induces DNA mutations , sister chromatid exchanges, unscheduled DNA synthesis, and DNA adduct formation (Holme et al., 1987; Kassie et al., 2001; Wild et al., 1986). In another example of how bacterial metabolites may influence CRC development, commensal bacteria of the Bacteroides genus generate ether-like polyunsaturated lipids such as fecapentaenes (de Kok et al., 1992), and a number of in vitro and in vivo studies have confirmed that fecapentaenes induce oxidative DNA damage through generation of 8-oxo-dG or directly alkylate DNA to form secondary mutagenic species (Huycke and Gaskins, 2004; Shioya et al., 1989; Zarkovic et al., 1993). "
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ABSTRACT: In recent years, our understanding of the mechanisms underlying colorectal carcinogenesis has vastly expanded. Underlying inflammation within the intestine, diet, and most recently, the gut microbiota, have been demonstrated to influence the development of colorectal cancer. However, since cancer is ultimately a genetic disease, these factors are thought to create genotoxic stress within the intestinal environment to promote genetic and epigenetic alterations leading to cancer. In this review, we will focus on how gut microbes intersect with inflammation, diet, and host genetics to influence the development of colon cancer.
Molecular cell 04/2014; 54(2):309-320. DOI:10.1016/j.molcel.2014.03.039 · 14.02 Impact Factor
Available from: Chi Chen
- "A broad MS-based metabolomics study that used GC-MS and LC-MS analyses, of intestinal digesta from conventional and germ-free mice revealed the significant contribution of bacterial metabolites to mammalian blood metabolites . In addition to their known effects in intestinal ailments, metabolic diseases, and immune diseases [67–69], gut flora can also affect XIT through indirect regulation of XMEs  or direct interference of xenobiotic metabolism [71, 72]. Because of the complexity and unpredictability of bacterial metabolism, it is expected that LC-MS-based metabolomics should be more effective than traditional metabolite analysis for examining the influences of xenobiotics on symbiotic gut flora in humans and animals. "
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ABSTRACT: Xenobiotic exposure, especially high-dose or repeated exposure of xenobiotics, can elicit detrimental effects on biological systems through diverse mechanisms. Changes in metabolic systems, including formation of reactive metabolites and disruption of endogenous metabolism, are not only the common consequences of toxic xenobiotic exposure, but in many cases are the major causes behind development of xenobiotic-induced toxicities (XIT). Therefore, examining the metabolic events associated with XIT generates mechanistic insights into the initiation and progression of XIT, and provides guidance for prevention and treatment. Traditional bioanalytical platforms that target only a few suspected metabolites are capable of validating the expected outcomes of xenobiotic exposure. However, these approaches lack the capacity to define global changes and to identify unexpected events in the metabolic system. Recent developments in high-throughput metabolomics have dramatically expanded the scope and potential of metabolite analysis. Among all analytical techniques adopted for metabolomics, liquid chromatography-mass spectrometry (LC-MS) has been most widely used for metabolomic investigations of XIT due to its versatility and sensitivity in metabolite analysis. In this review, technical platform of LC-MS-based metabolomics, including experimental model, sample preparation, instrumentation, and data analysis, are discussed. Applications of LC-MS-based metabolomics in exploratory and hypothesis-driven investigations of XIT are illustrated by case studies of xenobiotic metabolism and endogenous metabolism associated with xenobiotic exposure.
Computational and Structural Biotechnology Journal 03/2013; 4(5):e201301008. DOI:10.5936/csbj.201301008
Available from: Carl Alpert
- "In view of the fact that a considerable proportion of intestinal bacteria elude cultivation (Suau et al., 1999), the use of conventional enumeration techniques is insufficient to compare the microbiota of HMA animals and man. To overcome these limitations, some researchers concentrated on the characterization of the metabolic activities of the microbiota (Kassie et al., 2001; Mallett et al., 1987). Others used methods such as dotblot quantification of total RNA extracts with group specific probes (Edwards et al., 2003), whole-cell hybridization with fluorescently labeled 16S rRNAtargeted oligonucleotide probes (Gerard et al., 2004) or terminal restriction fragment length polymorphism (T- RFLP) analysis of 16S rRNA gene sequences (Kibe et al., 2005), which permit the culture-independent identification of intestinal bacteria (Vaughan et al., 2000). "
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ABSTRACT: Human microbiota associated rats are frequently used as a model to study host microbe interactions. This study investigated the long-term stability of the bacterial community in such rats. Following the association of two strains of germ-free rats (12 male animals each) with fecal bacteria from a human donor the development of the microbiota was monitored for 12 months by PCR-denaturing gradient gel electrophoresis. During this time the Dice similarity coefficient (Cs) for the fecal microbial community of the rats associated with a human microbiota in comparison to the donor sample ranged between 73% +/- 8 and 74% +/- 3 for the Wistar and the Fischer 344 rats, respectively. After 12 months the similarity coefficients were 78% +/- 9 and 76% +/- 7, respectively, while the similarity coefficients for rat sample replicates ranged from 77% +/- 7 to 88% +/- 5; the similarity coefficient of the donor sample replicates was 78% +/- 9. DNA sequences of bands observed in the different denaturing gradient gel electrophoresis profiles exhibited the highest degree of identity to uncultured bacteria previously found in samples of human, mouse or pig intestinal origin. The results of this study suggest that the dominant human fecal microbiota can be maintained in the human microbiota associated rat model for at least one year.
Current issues in molecular biology 01/2008; 10(1-2):17-24. · 5.75 Impact Factor
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