TY - JOUR
T1 - Differential induction of carcinogen metabolizing enzymes in a transgenic mouse model of fulminant hepatitis
AU - Chemin, Isabelle
AU - Takahashi, Satoru
AU - Belloc, Claire
AU - Lang, Matti A.
AU - Ando, Kazuki
AU - Guidotti, Luca G.
AU - Chisari, Francis V.
AU - Wild, Christopher P.
PY - 1996/9
Y1 - 1996/9
N2 - The objective of this work is to examine the possible modulation of carcinogen metabolism (activation by cytochrome P450s and detoxification by conjugation via glutathione S-transferases [GST]) in relation to hepatitis B virus (HBV)-associated liver injury. In HBV transgenic mouse lineage 107.5, the hepatitis B surface antigen (HBsAg) is expressed at noncytopathic concentrations but after injection of an HBsAg-specific, major histocompatibility complex (MHC) class I restricted cytotoxic T-lymphocyte (CTL) clone, the mice develop a severe acute necroinflammatory liver disease that reaches maximum severity within 3 days and gradually subsides during the next 2 to 3 weeks. In this model, using immunohistochemical analysis, we observed an increase of P450s (CYP1A and 2A5), both involved in aflatoxin B1 metabolism, but minor changes or no changes for others (2B, 2C, 2E, 3A). There was a fivefold decrease in the total liver P450 microsomal content 3 days' post-CTL injection with the result that the relative proportion of CYP2A5 and 1A compared with other P450s is increased. Individual microsomal P450 enzyme contents estimated by Western blotting; Northern blot analysis of liver CYP messenger RNA (mRNA) levels as well as in vitro metabolism of specific substrates for different P450 isoenzymes were consistent with the immunohistochemical data. Immunohistochemical staining with antibodies to cytosolic π class GST was increased 1 and 3 days postinjection followed by a progressive decrease at later time points (the same phenomenon was observed to a lesser extent for GST α). The activity of hepatic cytosols toward substrates specific for different subclasses of GST (μ, π, α) showed that while GST μ was not changed in the CTL-injected HBV transgenic mice, GST π and, to a lesser extent, α were increased as compared with controls. These results suggest that liver call injury induced by a process of acute fulminant-like hepatitis can lead to the induction of some carcinogen metabolizing enzymes notably, Cyp 1A, 2A5 and GST π in the mouse.
AB - The objective of this work is to examine the possible modulation of carcinogen metabolism (activation by cytochrome P450s and detoxification by conjugation via glutathione S-transferases [GST]) in relation to hepatitis B virus (HBV)-associated liver injury. In HBV transgenic mouse lineage 107.5, the hepatitis B surface antigen (HBsAg) is expressed at noncytopathic concentrations but after injection of an HBsAg-specific, major histocompatibility complex (MHC) class I restricted cytotoxic T-lymphocyte (CTL) clone, the mice develop a severe acute necroinflammatory liver disease that reaches maximum severity within 3 days and gradually subsides during the next 2 to 3 weeks. In this model, using immunohistochemical analysis, we observed an increase of P450s (CYP1A and 2A5), both involved in aflatoxin B1 metabolism, but minor changes or no changes for others (2B, 2C, 2E, 3A). There was a fivefold decrease in the total liver P450 microsomal content 3 days' post-CTL injection with the result that the relative proportion of CYP2A5 and 1A compared with other P450s is increased. Individual microsomal P450 enzyme contents estimated by Western blotting; Northern blot analysis of liver CYP messenger RNA (mRNA) levels as well as in vitro metabolism of specific substrates for different P450 isoenzymes were consistent with the immunohistochemical data. Immunohistochemical staining with antibodies to cytosolic π class GST was increased 1 and 3 days postinjection followed by a progressive decrease at later time points (the same phenomenon was observed to a lesser extent for GST α). The activity of hepatic cytosols toward substrates specific for different subclasses of GST (μ, π, α) showed that while GST μ was not changed in the CTL-injected HBV transgenic mice, GST π and, to a lesser extent, α were increased as compared with controls. These results suggest that liver call injury induced by a process of acute fulminant-like hepatitis can lead to the induction of some carcinogen metabolizing enzymes notably, Cyp 1A, 2A5 and GST π in the mouse.
UR - http://www.scopus.com/inward/record.url?scp=0029844863&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029844863&partnerID=8YFLogxK
U2 - 10.1053/jhep.1996.v24.pm0008781338
DO - 10.1053/jhep.1996.v24.pm0008781338
M3 - Article
C2 - 8781338
AN - SCOPUS:0029844863
VL - 24
SP - 649
EP - 656
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 3
ER -