Carcinogenesis, Vol 18, 2179-2190, Copyright © 1997 by Oxford University Press
P Chomarat, MA Sipowicz, BA Diwan, LW Fornwald, YC Awasthi, MR Anver, JM Rice, LM Anderson and CP Wild
Mice naturally infected by Helicobacter hepaticus develop a chronic active
hepatitis leading to hepatocellular carcinoma. This mouse model of liver
cancer was used to examine the impact of bacterial infection on the hepatic
expression and activity of enzymes involved in carcinogen bioactivation
(phase I enzymes) and detoxification (phase II enzymes). No major
differences in total cytochrome P450 (CYP) content were found between
control and infected mice during the course of the study. The most striking
modulations of individual isoenzymes were the increases in
immunohistochemical staining observed for CYP1A and CYP2A5 in relation to
increasing age and liver lesions. The increase in CYP2A5 in mice aged over
12 months was confirmed by the observed increases in coumarin
7-hydroxylation (CYP2A5 substrate) in vitro and CYP2A5 mRNA levels by
Northern blot analysis. Immunoblotting confirmed the specific induction of
CYP1A2 in infected mice 12 and 18 months of age. Perfusion of liver with
nitroblue tetrazolium, an indicator for superoxide formation, demonstrated
that in livers of infected mice, hepatocytes often co-expressed CYP2A5 and
formazan deposition. Concerning phase II enzymes, an enhancement of
glutathione S-transferase (GST) activities, related to the disease process,
was observed in infected mice. An age- specific increase of GSTpi and A4.4
(early stage of disease) and GST YaYa (>9 months) expression was also
demonstrated by immunohistochemical staining. In contrast, catalase and
glutathione- peroxidase activities, as well as reduced glutathione content
were decreased in the early stages of disease (3-9 months) in infected mice
compared to age-matched control mice. Overall, these results suggest that
alterations in CYP and GST expression may contribute to the aetiology of
tumour incidence due to H. hepaticus infection via production of reactive
oxygen species.
ARTICLES
Distinct time courses of increase in cytochromes P450 1A2, 2A5 and glutathione S-transferases during the progressive hepatitis associated with Helicobacter hepaticus
Unit of Environmental Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
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