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Rifampicin Suppresses Hepatic CYP2E1 Expression and Minimizes DNA Injury Caused by Carbon Tetrachloride in Perivenular Hepatocytes of Mice
Author(s) -
Takeda Kazuo,
Watanabe Jun,
Inoue Kyouichi,
Kanamura Shinsuke
Publication year - 2000
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2000.tb00019.x
Subject(s) - carbon tetrachloride , microbiology and biotechnology , dna fragmentation , cyp2e1 , chemistry , hepatocyte , liver injury , cytochrome , apoptosis , microsome , programmed cell death , biochemistry , biology , pharmacology , enzyme , in vitro , organic chemistry
Background: Rifampicin has been shown to increase during activities of serum transaminases and to decrease in cytochrome P‐450‐mediated monooxygenase activities in livers of mice treated with carbon tetrachloride (CC1 4 ). Although these findings suggest that rifampicin prevents hepatocyte damage caused by CC1 4 , detailed information on the protective effects is not available. Methods: We injected first rifampicin and then CC1 4 into mice and examined denaturation and fragmentation of hepatocyte DNA by in situ nick translation, in situ end labeling, and in situ hybridization. Furthermore, expressions of p53, a cytoplasmic marker for apoptosis, and bc12, an anticell death factor, were examined immunohistochemically. In addition, a major ethanol‐inducible P‐450 isoform in liver homogenates or microsomes, CYP2E1, was examined by Western blotting, because the enzyme metabolizes CCl 4 and forms free radicals to injure perivenular hepatocytes in which the enzyme is restrictedly expressed. Results: Rifampicin prevented the denaturation and fragmentation of DNA caused by CCl 4 in perivenular hepatocytes except for those located within two or three cell layers surrounding the central venule. Furthermore, CYP2E1 decreased in liver homogenates or microsomes from rifampicin‐treated animals. It is therefore likely that rifampicin suppresses expression of CYP2E1 and protects CCl 4 ‐mediated DNA damage of hepatocytes by inhibiting formation of free radicals. In addition, perivenular hepatocytes except for those surrounding the venule showed negative immunoreaction for p53 and bc12 in rifampicin+CCl 4 ‐treated animals. Conclusions: The drug did not alter the mechanism of cell death from necrosis to apoptosis and did notpromote recovery of hepatocytes from CCl 4 ‐mediated damage.