Distinct time courses of increase in cytochromes P450 1A2, 2A5 and glutathione S-transferases during the progressive hepatitis associated with Helicobacter hepaticus.
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.
Chomarat
P
P
Unit of Environmental Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Sipowicz
M A
MA
Diwan
B A
BA
Fornwald
L W
LW
Awasthi
Y C
YC
Anver
M R
MR
Rice
J M
JM
Anderson
L M
LM
Wild
C P
CP
D000367:Age Factors; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D000072467:Cytochrome P450 Family 2; D005982:Glutathione Transferase / Q000096:biosynthesis*; D016481:Helicobacter Infections / Q000150:complications / Q000201:enzymology*; D006521:Hepatitis, Chronic / Q000150:complications / Q000201:enzymology*; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000209:etiology; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D005982:Glutathione Transferase