Striking LD50 variation associated with fluctuations of CYP2E1-positive cells in hepatic lobule during chronic CCl4 exposure in mice.
Intraperitoneal injection of serially diluted carbon tetrachloride (CCl(4)) from 0.2 to 2.0 ml/kg produced an LD(50) value of 0.46 ml/kg in the normal mouse. Following repeated administration of 0.2 ml/kg CCl(4) twice a week for 1 and 3 months, the LD(50) values were over 2.0 and 0.72 ml/kg, respectively. A single administration of 0.2 ml/kg CCl(4) induced, within 24 h, apoptotic death of liver cells in the centrilobular zone 3 that were observed positive in cytochrome P450 2E1 (CYP2E1). However, after repeated exposure to 0.2 ml/kg twice a week for 1 month, cells in the centrilobular area were almost completely replaced with CYP2E1-negative cells. These cells were tolerant to CCl(4). After 3 months of exposure, a considerable number of CYP2E1-positive hepatocytes were observed throughout the periportal zone 1 and intermediate zone 2. Thus, fluctuations in CYP2E1-positive cells during chronic exposure to low doses of CCl(4) induced tolerance, which can be partially lost after prolonged CCl(4) exposure.
Irie
Hiroshi
H
Department of Anatomy, Teikyo University School of Medicine, Kaga 2-11-1, Itabash-Ku, Tokyo 173-8605, Japan. iriehiro@med.teikyo.u-ac.jp
Asano-Hoshino
Anshin
A
Sekino
Yoshihisa
Y
Nogami
Makoto
M
Kitagawa
Tomoyuki
T
Kanda
Hiroaki
H
D000208:Acute Disease; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride / Q000494:pharmacology / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D002908:Chronic Disease; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007928:Lethal Dose 50; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase