Genotoxicity of acrylamide and glycidamide in human lymphoblastoid TK6 cells

Naoki, Katsuhiko; Sakamoto, Hiroko; Sakuraba, Mayumi; Koizumi, Tomoko; Takashima, Yoshio; Hayashi, Makoto; Matsufuji, Hiroshi; Yamagata, Kazuo; Masuda, S.; Kinae, Naohide; Honma, Masamitsu

doi:10.1016/j.mrgentox.2005.11.006

Cited by 74 publications

(52 citation statements)

References 34 publications

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“…Compared to AA, GA (2-4 mM) was much more mutagenic, about 5-10-fold more potent. This is consistent with several previously reported genotoxicity studies conducted using mammalian cells (Baum et al, 2005;Besaratinia and Pfeifer, 2003;Koyama et al, 2006;Martins et al, 2006). Since the genotoxic responses at higher concentration are reproducible, LOH analysis of the mutants induced by 4 mM GA and 16 mM AA treatments was conducted to determine the types of the mutations.…”

Section: Discussionsupporting

confidence: 89%

“…The genotoxicity of AA has been studied extensively, but there are fewer experimental data available with GA as the test substance (Baum et al, 2005;Besaratinia and Pfeifer, 2004;Koyama et al, 2006;Martins et al, 2006;Paulsson et al, 2003). AA is not mutagenic in bacterial assays, and it is mutagenic in mammalian somatic and germinal cells in vitro and in vivo (Dearfield et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Genotoxic effects of acrylamide and glycidamide in mouse lymphoma cells

Mei

Churchwell

et al. 2008

Food and Chemical Toxicology

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In addition to occupational exposures to acrylamide (AA), concerns about AA health risks for the general population have been recently raised due to the finding of AA in food. In this study, we evaluated the genotoxicity of AA and its metabolite glycidamide (GA) in L5178Y/ Tk +/− mouse lymphoma cells. The cells were treated with 2-18 mM of AA or 0.125-4 mM of GA for 4 h without metabolic activation. The DNA adducts, mutant frequencies and the types of mutations for the treated cells were examined. Within the dose range tested, GA induced DNA adducts of adenine and guanine [N3-(2-carbamoyl-2-hydroxyethyl)-adenine and N7-(2-carbamoyl-2-hydroxyethyl)-guanine] in a linear dose-dependent manner. The levels of guanine adducts were consistently about 60-fold higher across the dose range than those of adenine. In contrast, no GAderived DNA adducts were found in the cells treated with any concentrations of AA, consistent with a lack of metabolic conversion of AA to GA. However, the mutant frequency was significantly increased by AA at concentrations of 12 mM and higher. GA was mutagenic starting with the 2 mM dose, suggesting that GA is much more mutagenic than AA. The mutant frequencies were increased with increasing concentrations of AA and GA, mainly due to an increase of proportion of small colony mutants. To elucidate the underlying mutagenic mechanism, we examined the loss of heterozygosity (LOH) at four microsatellite loci spanning the entire chromosome 11 for mutants induced by AA or GA. Compared to GA induced mutations, AA induced more mutants whose LOH extended to D11Mit22 and D11Mit74, an alteration of DNA larger than half of the chromosome. Statistical analysis of the mutational spectra revealed a significant difference between the types of mutations induced by AA and GA treatments (P = 0.018). These results suggest that although both AA and GA generate mutations through a clastogenic mode of action in mouse lymphoma cells, GA induces mutations via a DNA adduct mechanism whereas AA induces mutations by a mechanism not involving the formation of GA adducts.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Genotoxic effects of acrylamide and glycidamide in mouse lymphoma cells

Mei

Churchwell

et al. 2008

Food and Chemical Toxicology

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“…The mutagenic activity induced by GA is much more potent than that of AA not only at the HPRT locus, but also at the TK locus (30,31,34,37). Moreover, LOH analysis of the TK gene showed most GA-induced TK mutants were the non-LOH type in human lymphoblastoid TK6 cells (31), suggesting the induction of primarily point mutations for GA.…”

Section: Mammalian Gene Mutation Assays At the Hprt And Tk Locimentioning

confidence: 99%

“…Other than the disrupted mutation results from HPRT locus, the results obtained at TK gene demonstrate a relatively consistent mutagenic potential not only induced by GA, but also induced by AA, which is considered to be a promutagen at HPRT locus. As early as 1987, Moore et al (31). It should be noted that these weakly or mildly positive responses at the TK gene were obtained independently of the addition of exogenous metabolic activation systems.…”

Section: Mammalian Gene Mutation Assays At the Hprt And Tk Locimentioning

confidence: 99%

“…AA in vitro induces chromosomal aberrations, micronuclei, sister chromatid exchanges and mitotic disturbance with or without the metabolic activation. It also induces positive responses in the TK locus in vivo and in vitro (18,(28)(29)(30)(31)38). Further analysis of Tk mutants in mouse lymphoma cells showed AA induced almost exclusively small-colony mutants, which appear to represent chromosome alterations to that chromosome 11 carring the Tk locus (28).…”

Section: Mammalian Gene Mutation Assays At the Hprt And Tk Locimentioning

confidence: 99%

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Genotoxicity of Acrylamide and Glycidamide: A Review of the Studies by HPRT Gene and TK Gene Mutation Assays

Cao

2012

Genes and Environment

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Acrylamide (AA), a proven rodent carcinogen, is found in a variety of commonly consumed human foods, which has raised public health concerns. AA is largely oxidized to the chemically reactive epoxide, glycidamide (GA), by cytochrome P450 2E1. The genotoxic eŠects of AA and GA have been extensively evaluated. However, the results in mammalian gene mutation tests were inconsistent, especially the genotoxic eŠects at the HPRT gene and TK gene. In this article, the relevant mutations induced by AA and GA on both gene loci in various test systems involving in vivo and in vitro tests are reviewed. It is conˆrmed that AA acts directly as a clastogen and produces weakly mutagenic eŠects at the HPRT gene probably by metabolic conversion of AA to GA. On the other hand, GA is a strong mutagen with high reactivity to DNA, inducing predominantly point mutations. The molecular mutation spectra of AA and GA at the HPRT and TK genes are also compared and summarized here, for better clarifying the mechanisms of mutation induced by these two compounds. These data would help to understand the mutagenicity of AA and its contribution to human cancers.

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Food Deep‐Fat Frying

Bouchon

2011

Food Processing Handbook

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Genotoxicity of acrylamide and glycidamide in human lymphoblastoid TK6 cells

Cited by 74 publications

References 34 publications

Genotoxic effects of acrylamide and glycidamide in mouse lymphoma cells

Genotoxic effects of acrylamide and glycidamide in mouse lymphoma cells

Genotoxicity of Acrylamide and Glycidamide: A Review of the Studies by HPRT Gene and TK Gene Mutation Assays

Food Deep‐Fat Frying

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