Metallothionein overexpression suppresses hepatic hyperplasia induced by hepatitis B surface antigen.
Transgenic mice that express the viral coat proteins of hepatitis B virus (HBV) in the liver display hepatocellular damage, inflammation, regeneration, hyperplasia, and, eventually, neoplasia that is similar to that of people with chronic, active hepatitis caused by HBV infection. Hepatocellular regeneration, in the context of chronic injury and inflammation, is thought to expose dividing cells to excessive oxygen radicals, which are believed to lead to DNA damage and, ultimately, neoplasia. Because metallothioneins scavenge free radicals in vitro, we generated mice that express excess (>10-fold) metallothionein I (MT-I* mice) and the HBV surface antigens (HBsAg) to ascertain whether MT-I* would ameliorate aspects of the pathology induced by HBsAg. Markers of hepatocyte injury and tumorigenesis in HBsAg mice were compared to those in double transgenic (HBsAg and MT-I*) mice. Hepatic hyperplasia, histology, aneuploidy, and accumulation of an oxidative DNA adduct, 8-oxo-2'-deoxyguanosine, were examined. Although hepatitis and neoplasia were not prevented by MT-I* expression in the HBsAg mice, there was less hyperplasia and less aneuploidy. We conclude that MT-I produces a beneficial effect in this in vivo model of HBV-induced hepatitis.
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, Washington, 98195, USA.
C J
CJ
Quaife
R L
RL
Cherne
T G
TG
Newcomb
R P
RP
Kapur
R D
RD
Palmiter
D000818:Animals; D002104:Cadmium / Q000378:metabolism; D002106:Cadmium Radioisotopes; D003300:Copper / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000096:biosynthesis / Q000235:genetics / Q000633:toxicity*; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D002106:Cadmium Radioisotopes; D006514:Hepatitis B Surface Antigens; D012333:RNA, Messenger; D002104:Cadmium; D003300:Copper; D008668:Metallothionein; D015032:Zinc