Formation of N-7-(2-carbamoyl-2-hydroxyethyl)guanine in DNA of the mouse and the rat following intraperitoneal administration of [14C]acrylamide

ArticleinCarcinogenesis 16(5):1161-5 · June 1995with22 Reads
DOI: 10.1093/carcin/16.5.1161 · Source: PubMed
Acrylamide is an alkylating agent which reacts very slowly in direct reactions with DNA and is negative in the Ames test, but is carcinogenic in mice and rats. In order to explain the cancer-initiating properties of acrylamide we have studied DNA adduct formation in vitro with a metabolizing system and in vivo in mice and rats following i.p. administration of 14C-labeled acrylamide. A major adduct found in both species was N-7-(2-carbamoyl-2-hydroxy-ethyl)guanine, formed by reaction of the DNA with the epoxide metabolite glycidamide. The levels of this adduct were similar in the different organs of the two rodent species, which supports the notion that glycidamide is relatively evenly distributed among tissues and that the organ-specificity in acrylamide carcinogenesis cannot be explained by a selective accumulation of the DNA-reactive metabolite in target organs.
    • "Ample in vitro and in vivo animal studies have shown that acrylamide, mainly after metabolic conversion to glycidamide by the enzyme cytochrome P4502E1 (CYP2E1), causes chromosomal damage (aberrations, micronuclei, aneuploidy) and mutagenic effects [4]. However, the tissues with most DNA adducts or DNA mutations do not consistently correspond to the tissues in which cancer occurred in the rat studies [5,6] and, more and more, other mechanisms of acrylamide carcinogenesis are being proposed [7,8]. Animal studies have shown positive dose-response relations between acrylamide intake through drinking water and cancer in multiple organs in mice and rats, such as the mammary glands, thyroid gland, testes and the uterus [4]. "
    Dataset · Dec 2015 · Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
    • "Thyroid follicular cell carcnomas and adenomas were increased in a dose dependent manner at 1.5 and 3 mg/kg/day in female rats and at 0.5, 1.5, and 3 mg/kg/ day in male rats. Glycidamide, the reactive metabolite of acrylamide, forms adducts on reaction with DNA and is thought to be involved in the genotoxicity of acrylamide, and may lead to the carcinogenicity of acrylamide (Dearfield et al., 1988Dearfield et al., , 1995 Doerge et al., 2005; Ghanayem et al., 2005; Segerbä ck et al., 1995; Von Tungeln et al., 2012; Zeiger et al., 2009 ). The extent of AAVal adduct formation is associated with the area under the curve for acrylamide in blood, which is dependent on the dose administered, and the extent of metabolism (Calleman et al., 1993; Fennell et al., 2005). "
    [Show abstract] [Hide abstract] ABSTRACT: Acrylamide is an industrial chemical used to manufacture polymers, and is produced in foods during cooking at high heat. Hemoglobin adducts provide a long-lived dosimeter for acrylamide and glycidamide. This study determined acrylamide and glycidamide hemoglobin adducts (AAVal and GAVal) during a lifetime carcinogenesis bioassay. Exposure to acrylamide in drinking water began in utero in pregnant rats on gestation day (GD) 6. Dams were administered acrylamide until weaning, and male and female F1 rats were exposed for a further 104 weeks. Acrylamide concentration in drinking water was adjusted to provide a constant dose of 0.5, 1.5, and 3 mg/kg/day. Blood was collected from animals euthanized at 2, 60, 90 and 120 days and 53, 79, and 104 weeks after weaning. Low levels of AAVal and GAVal at postnatal day (PND) 24 suggested that little exposure to acrylamide occurred by placental or lactational transfer, and extensive metabolism to glycidamide occurred with a GAVal:AAVal ratio of 4. Adduct levels varied somewhat from 60 days - 2 years, with a GAVal:AAVal ratio of approximately 1. Adduct formation/day estimated at each timepoint at 3 mg/kg/day for AAVal was 1293 ± 220 and 1096 ± 338 fmol/mg/day for male and female rats, respectively. Adduct formation per day estimated at each timepoint at 3 mg/kg/day for GAVal was 827 ± 78 fmol/mg/day for male rats, and 982 ± 222 fmol/mg/day for female rats. The study has provided estimates of linearity for dose response, and variability in internal dose throughout an entire 2-year bioassay, including the early phases of pregnancy and lactation. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology.
    Full-text · Article · Jul 2015
    • "When assessed in calf thymus DNA in vitro, acrylamide has been found to itself react very slowly with the DNA, predominantly reacting at the N − 1 of adenine [42] . In rats and mice exposed to 14 Cradiolabelled acrylamide [33], the predominant adduct formed by glycidamide is N-7(2-carbamoyl-2-hydroxyethyl)-guanine and to a lesser extent N3-(2-carbamoyl-2-hydroxyethyl)-adenine (N3- GA-Ade) glycidamide forms other DNA adducts in vitro. Both glycidamide, and to a lesser extent acrylamide, induce DNA strand breaks in cellular DNA via adduct formation. "
    [Show abstract] [Hide abstract] ABSTRACT: Acrylamide is a toxin that humans are readily exposed to due to its formation in many carbohydrate rich foods cooked at high temperatures. Acrylamide is carcinogenic, neurotoxic and causes reproductive toxicity when high levels of exposure are reached in mice and rats. Acrylamide induced effects on fertility occur predominantly in males. Acrylamide exerts its reproductive toxicity via its metabolite glycidamide, a product which is only formed via the cytochrome P450 detoxifying enzyme CYP2E1. Glycidamide is highly reactive and forms adducts with DNA. Chronic low dose acrylamide exposure in mice relevant to human exposure levels results in significantly increased levels of DNA damage in terms of glycidamide adducts in spermatocytes, the specific germ cell stage where Cyp2e1 is expressed. Since cells in the later stages of spermatogenesis are unable to undergo DNA repair, and this level of acrylamide exposure causes no reduction in fertility, there is potential for this damage to persist until sperm maturation and fertilisation. Cyp2e1 is also present within epididymal cells, allowing for transiting spermatozoa to be exposed to glycidamide. This could have consequences for future generations in terms of predisposition to diseases such as cancer, with growing indications that paternal DNA damage can be propagated across multiple generations. Since glycidamide is the major contributor to DNA damage, a mechanism for preventing these effects is inhibiting the function of Cyp2e1. Resveratrol is an example of an inhibitor of Cyp2e1 which has shown success in reducing damage caused by acrylamide treatment in mice. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.
    Full-text · Article · Apr 2015
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