Isomer-specific acute toxicity and cell proliferation in livers of B6C3F1 mice exposed to dichlorobenzene.
The acute hepatotoxicity of isomers of dichlorobenzene (o-, m-, and p-DCB) was compared in livers of male B6C3F1 mice at different time points after a single intragastric administration. The highest doses of o-, m-, and p-DCB administered, 300, 300, and 1800 mg/kg, respectively, are below the lethal range. Acute hepatic injury was assessed by serum alanine aminotransferase (ALT) activity and hepatic histology. Hepatocyte replication was estimated by means of immunohistochemical demonstration of BrdU-labeled cells. Both o-DCB and m-DCB at a dose of 300 mg/kg produced significant elevations of liver weight and ALT activity as well as extensive liver cell necrosis. In contrast, p-DCB at a highest dose of 1800 mg/kg induced slight hepatocyte injury. Dose-response studies indicated that the rank order for acute hepatotoxicity of the isomers was m-DCB > o-DCB > or = p-DCB. However, p-DCB induced hepatocyte cell proliferation in spite of the lack of manifest hepatotoxicity. In contrast, increases of cell proliferation due to o- or m-DCB exposure occurred only after dosages that caused hepatic injury. These data suggest the hepatocyte proliferation induced by o- or m-DCB is compensatory regeneration while that induced by p-DCB is a response to mitogenic stimulation.
Umemura
T
T
Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan.
Saito
M
M
Takagi
A
A
Kurokawa
Y
Y
D000208:Acute Disease; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D002722:Chlorobenzenes / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007536:Isomerism; D008099:Liver / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012680:Sensitivity and Specificity
D002722:Chlorobenzenes; C004726:2-dichlorobenzene; C042146:1,3-dichlorobenzene; C018511:4-dichlorobenzene; D000410:Alanine Transaminase