Striking LD₅₀ variation associated with fluctuations of CYP2E1-positive cells in hepatic lobule during chronic CCl₄ exposure in mice

摘要

Intraperitoneal injection of serially diluted carbon tetrachloride (CCl₄) from 0.2 to 2.0 ml/kg produced an LD₅₀ value of 0.46 ml/kg in the normal mouse. Following repeated administration of 0.2 ml/kg CCl₄ twice a week for 1 and 3 months, the LD₅₀ values were over 2.0 and 0.72 ml/kg, respectively. A single administration of 0.2 ml/kg CCl₄ 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 CCl₄. 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 CCl₄ induced tolerance, which can be partially lost after prolonged CCl₄ exposure.