title: Mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in colon and liver of Big Blue rats: role of DNA adducts, strand breaks, DNA repair and oxidative stress.
abstract: The contribution of oxidative stress, different types of DNA damage and expression of DNA repair enzymes in colon and liver mutagenesis induced by 2-amino-3-methylimidazo [4,5-f]quinoline (IQ) was investigated in four groups of six Big Blue rats fed diets with 0, 20, 70, and 200 mg IQ/kg for 3 weeks. There were dose-response relationships of DNA adducts ((32)P-postlabeling) and DNA strand breaks (comet assay) in colon and liver tissues, with the highest levels of DNA adducts and strand breaks in the colon. There was dose-dependent induction of mutations in both the colon and the liver, and the same IQ dose produced two-fold more cII mutations in the liver compared with the colon. The IQ-induced mutation spectrum in the colon was not significantly different to that of control rats. The expression of ERCC1 and OGG1 was higher in the colon than liver, and was unaffected by the IQ diet. Investigations of oxidative stress biomarkers produced inconclusive results. Oxidative DNA damage detected by the endonuclease III enzyme and 7-hydro-8-oxo-2'-deoxyguanosine in colon, liver and/or urine was unaltered by IQ. However, there was increased level of gamma-glutamyl semialdehyde in liver proteins, indicating a higher rate of protein oxidation in the liver following IQ administration. In plasma and erythrocytes there were unaltered levels of oxidized protein, malondialdehyde, and antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, catalase, glutathione reductase) indicating no systemic oxidative stress. However, the level of total vitamin C was increased in plasma, with the largest fraction being in the reduced form. In conclusion, our results indicate that DNA adducts rather than oxidative stress are responsible for the initiation of IQ-induced carcinogenesis of the liver and colon. A lower frequency of mutations in the colon than in the liver could be related to higher expression of DNA repair enzymes in the former.
authors.affiliation: Institute of Public Health (c/o Department of Pharmacology), The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Møller
authors.forename: Håkan
authors.initials: H
authors.lastname: Wallin
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
authors.forename: Herman
authors.initials: H
authors.lastname: Autrup
authors.forename: Lotte
authors.initials: L
authors.lastname: Risom
authors.forename: Mikkel T
authors.initials: MT
authors.lastname: Hald
authors.forename: Bahram
authors.initials: B
authors.lastname: Daneshvar
authors.forename: Lars O
authors.initials: LO
authors.lastname: Dragsted
authors.forename: Henrik E
authors.initials: HE
authors.lastname: Poulsen
authors.forename: Steffen
authors.initials: S
authors.lastname: Loft
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D001483:Base Sequence; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D017931:DNA Primers; D004260:DNA Repair; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009153:Mutagens / Q000633:toxicity*; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D011804:Quinolines / Q000633:toxicity*; D051381:Rats; D011922:Rats, Mutant Strains
chemical_list: D017931:DNA Primers; D009153:Mutagens; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D001205:Ascorbic Acid