title: Lobe-specific increases in malondialdehyde DNA adduct formation in the livers of mice following infection with Helicobacter hepaticus.
abstract: Helicobacter hepaticus infection is associated with chronic hepatitis and the development of liver tumours in mice. The underlying mechanism of this liver carcinogenesis is not clear but the oxidative stress associated with H. hepaticus infection may result in induction of lipid peroxidation and the generation of malondialdehyde. Malondialdehyde can react with deoxyguanosine in DNA resulting in the formation of the cyclic pyrimidopurinone N-1,N(2) malondialdehyde-deoxyguanosine (M1dG) adduct. This adduct has the potential to cause mutations that may ultimately lead to liver carcinogenesis. The objective of this study was to determine the control and infection-related levels of M1dG in the liver DNA of mice over time, using an immunoslot-blot procedure. The level of M1dG in control A/J mouse livers at 3, 6, 9 and 12 months averaged 37.5, 36.6, 24.8 and 30.1 adducts per 10(8) nucleotides, respectively. Higher levels of M1dG were detected in the liver DNA of H. hepaticus infected A/JCr mice, with levels averaging 40.7, 47.0, 42.5 and 52.5 adducts per 10(8) nucleotides at 3, 6, 9 and 12 months, respectively. There was a significant age dependent increase in the level of M1dG in the caudate and median lobes of the A/JCr mice relative to control mice. A lobe specific distribution of the M1dG adduct in both infected and control mice was noted, with the left lobe showing the lowest level of the adduct compared with the right and median lobes at all time points. In a separate series of mice experimentally infected with H. hepaticus, levels of 8-hydroxy-deoxyguanosine were significantly greater in the median compared with the left lobe at 12 weeks after treatment. In conclusion, these results suggest that M1dG occurs as a result of oxidative stress associated with H. hepaticus infection of mice, and may contribute to liver carcinogenesis in this model.
authors.affiliation: Medical Research Council, Toxicology Unit, Hodgkin Building, University of Leicester, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK. rs25@le.ac.uk
authors.forename: R
authors.initials: R
authors.lastname: Singh
authors.forename: C
authors.initials: C
authors.lastname: Leuratti
authors.forename: S
authors.initials: S
authors.lastname: Josyula
authors.forename: M A
authors.initials: MA
authors.lastname: Sipowicz
authors.forename: B A
authors.initials: BA
authors.lastname: Diwan
authors.forename: K S
authors.initials: KS
authors.lastname: Kasprzak
authors.forename: H A
authors.initials: HA
authors.lastname: Schut
authors.forename: L J
authors.initials: LJ
authors.lastname: Marnett
authors.forename: L M
authors.initials: LM
authors.lastname: Anderson
authors.forename: D E
authors.initials: DE
authors.lastname: Shuker
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000378:metabolism*; D016481:Helicobacter Infections / Q000378:metabolism* / Q000382:microbiology; D008099:Liver / Q000737:chemistry*; D008297:Male; D008315:Malondialdehyde / Q000737:chemistry*; D051379:Mice
chemical_list: D018736:DNA Adducts; D008315:Malondialdehyde; D004247:DNA