Interactions of Fungal and Plant Toxins with DNA: Aflatoxins, Sterigmatocystin, Safrole, Cycasin, and Pyrrolizidine Alkaloids

Groopman, John D.; Cain, Lawrence G.

doi:10.1007/978-3-642-74775-5_10

Cited by 10 publications

(12 citation statements)

References 47 publications

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“…The other positive control, AFB1, also produced strand breaks in uninduced hepatocytes with an induced slope of 0.075 Ϯ 0.010 (n ϭ 4). AFB1 gave a positive response in only one experiment out of four in induced rat hepatocytes; this weak response is likely due to the induction of Phase II detoxification enzymes or Phase I enzymes that metabolize AFB1 to non-DNA binding metabolites [Groopman and Cain, 1990]. A positive response in the alkaline elution assay may be due to single-strand breaks at sites of DNA excision-repair processes, DNA singleor double-strand breaks per se, or lesions such as abasic sites that labilize the phosphodiester bond at the alkaline pH and are converted to strand breaks after exposure of DNA to alkali during the elution procedure.…”

Section: Analysis Of Dna Single-strand Breaks and Dna Adducts In Rat mentioning

confidence: 95%

Genotoxicity of naturally occurring indole compounds: correlation between covalent DNA binding and other genotoxicity tests

Reddy

Storer

Laws

et al. 2002

Environ and Mol Mutagen

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3-Methylindole (3MI), melatonin (Mel), serotonin (Ser), and tryptamine (Tryp) were evaluated in vitro for their potential to induce DNA adducts, DNA strand breaks, chromosomal aberrations (Abs), inhibition of DNA synthesis, and mutations. All compounds produced DNA adducts in calf thymus DNA in the presence of rat liver S9. In cultured rat hepatocytes, all produced DNA adducts but none induced DNA strand breaks. In Chinese hamster ovary cells, 3MI and Mel produced DNA adducts, Abs, and inhibition of DNA synthesis with and without S9, except that Mel without S9 did not form adducts. Ser formed DNA adducts, was an equivocal Abs inducer, and suppressed DNA synthesis. Tryp induced neither adducts nor Abs, but did suppress DNA synthesis with S9. Ser and Tryp were less cytotoxic than 3MI and Mel. Mel, Ser, and Tryp failed to induce mutations in Salmonella and E. coli strains with or without S9. 3MI and Mel produced DNA adducts but not mutations in Salmonella TA100 with S9. 3MI and its metabolite indole 3-carbinol also did not induce mutations in a shuttle vector system in human cells. The lack of correlation between DNA adducts and other genotoxicity endpoints for these indole compounds may be due to the higher sensitivity of the (32)P-postlabeling adduct assay or it may indicate that the indole-DNA adducts per se are not mutagenic and are not able to induce strand breaks or alkali-labile lesions. The indole-induced Abs may result from cytotoxicity and suppression of DNA synthesis with minimal if any contribution from DNA adducts.

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Section: Analysis Of Dna Single-strand Breaks and Dna Adducts In Rat mentioning

confidence: 95%

Genotoxicity of naturally occurring indole compounds: correlation between covalent DNA binding and other genotoxicity tests

Reddy

Storer

Laws

et al. 2002

Environ and Mol Mutagen

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“…The guanosine moieties are the reactive sites, where the intermediate is covalently bound. The major DNA adduct in vivo was the 8,9-dihydro-8-(N 7 -guanyl)-9-hydroxyaflatoxin B 1 (Groopman and Cain, 1990). Formation of DNA adducts correlated to mutagenicity, SCE induction, clastogenicity and recombinogenic effects.…”

Section: Significant Endogenous Mutagens/carcinogensmentioning

confidence: 99%

“…But neoplastic formations in other organs were also induced. Details, such as the sensitivity of animals, dose, route of administration and the role of the factors, can be found in reviews by Tazima (1982) and Groopman and Cain (1990). Circumstantial evidence from epidemiological studies indicates a causal relationship between the incidence of primary liver cancer in humans and the mean daily intake of AF B 1 (Tazima, 1982).…”

Section: Significant Endogenous Mutagens/carcinogensmentioning

confidence: 99%

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Molecular Modes of Action of Defensive Secondary Metabolites

Wink

Schimmer

2010

Functions and Biotechnology of Plant Secondary Metabolites

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Secondary metabolites (SM) have been shaped by evolution for more than 500 million years. As a result, many of them have distinctive biochemical and pharmacological properties. The molecular modes of action of the main groups of SM are reviewed in this chapter. Details are given on interactions of SM with proteins that can induce conformational changes and thus a modification of their bioactivity. The fluidity and permeability of biomembranes constitute another important target, which is influenced by many lipophilic and amphiphilic SM. A number of SM can either alkylate or intercalate DNA, which can cause mutations and in consequence cancer or malformations. Many SM are cytotoxic because they interfere with biomembranes, proteins of the cytoskeleton or DNA; they often induce programmed cell death (apoptosis). A large number of SM, especially alkaloids modulate neuronal signal transduction by interfering with ion channels, ion pumps, neuroreceptors, choline esterase, monoamine oxidase and other enzymes related to signal transduction pathways. A typical feature of SM is their ability to modulate more than one molecular target; thus, additive and even synergistic activities can be expected.

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“…Included among these agents are aflatoxin and the aromatic and heterocyclic amines. Aflatoxin is a potent hepatocarcinogen produced by fungal contamination of foods and readily forms DNA adducts (442). The heterocyclic and aromatic amines also readily form DNA adducts and have widespread industrial uses and occur in foodstuffs, cooked meat, and tobacco smoke (443,444).…”

Section: The Spindle Checkpointmentioning

confidence: 99%

Cell cycle control, checkpoint mechanisms, and genotoxic stress.

Shackelford

Kaufmann

Paules

1999

Environ Health Perspect

183

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The ability of cells to maintain genomic integrity is vital for cell survival and proliferation. Lack of fidelity in DNA replication and maintenance can result in deleterious mutations leading to cell death or, in multicellular organisms, cancer. The purpose of this review is to discuss the known signal transduction pathways that regulate cell cycle progression and the mechanisms cells employ to insure DNA stability in the face of genotoxic stress. In particular, we focus on mammalian cell cycle checkpoint functions, their role in maintaining DNA stability during the cell cycle following exposure to genotoxic agents, and the gene products that act in checkpoint function signal transduction cascades. Key transitions in the cell cycle are regulated by the activities of various protein kinase complexes composed of cyclin and cyclin-dependent kinase (Cdk) molecules. Surveillance control mechanisms that check to ensure proper completion of early events and cellular integrity before initiation of subsequent events in cell cycle progression are referred to as cell cycle checkpoints and can generate a transient delay that provides the cell more time to repair damage before progressing to the next phase of the cycle. A variety of cellular responses are elicited that function in checkpoint signaling to inhibit cyclin/Cdk activities. These responses include the p53-dependent and p53-independent induction of Cdk inhibitors and the p53-independent inhibitory phosphorylation of Cdk molecules themselves. Eliciting proper Gl, S, and G2 checkpoint responses to double-strand DNA breaks requires the function of the Ataxia telangiectasia mutated gene product. Several human heritable cancer-prone syndromes known to alter DNA stability have been found to have defects in checkpoint surveillance pathways. Exposures to several common sources of genotoxic stress, including oxidative stress, ionizing radiation, UV radiation, and the genotoxic compound benzo[alpyrene, elicit cell cycle checkpoint responses that show both similarities and differences in their molecular signaling. -Environ Health Perspect 107(Suppl 1):5-24 (1999 (Figure 1) (6,8).The description of the cell cycle being divided into four phases led to many questions about the regulatory mechanisms cells employ to ensure an ordered and sequential progression from G1 to M phase, as well as the mechanisms ensuring DNA stability. Some of these questions were summarized as the "completion" and "alternation" problems (8,9). In the completion problem, the question is raised as to how cells ensure that specific events are completed before subsequent events are initiated. For example, cells must ensure that once DNA is condensed for segregation during cytokinesis, it remains condensed throughout M phase and does not prematurely decondense. In the alternation problem, the question is raised as to how cells ensure that once an event is completed, it is not inappropriately repeated. For example, cells must ensure that once DNA replication in S phase is completed, it is followed by DNA co...

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Interactions of Fungal and Plant Toxins with DNA: Aflatoxins, Sterigmatocystin, Safrole, Cycasin, and Pyrrolizidine Alkaloids

Cited by 10 publications

References 47 publications

Genotoxicity of naturally occurring indole compounds: correlation between covalent DNA binding and other genotoxicity tests

Genotoxicity of naturally occurring indole compounds: correlation between covalent DNA binding and other genotoxicity tests

Molecular Modes of Action of Defensive Secondary Metabolites

Cell cycle control, checkpoint mechanisms, and genotoxic stress.

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