Effect of phenobarbital on intralobular expression of CYP2B1/2 in livers of rats - Difference in the expression between single and repetitive administrations

Phenobarbital (PB) was shown to induce the major PB-inducible cytochrome P4 50 (CYP) isoforms, CYP2B1/2, in perivenular hepatocytes by a single injecti on, and in midzonal and periportal hepatocytes in addition to perivenular h epatocytes by injections of the same dosage once a day for 3 days in rat li vers. The present study was undertaken to determine whether the spread of e nzyme induction to midzonal and periportal hepatocytes is caused by the inc rease in total dose of the drug by repetitive injections or by the repetiti ve injections of the drug themselves. Male adult rats were administered PB by a single injection (80 mg/kg) or repetitive injections (20 mg/kg once a day for 4 days; a total dose of 80 mg/kg), and the molar content of CYP2B1/ 2 was measured by quantitative immunohistochemistry in the cytoplasm of per ivenular, midzonal, and periportal hepatocytes. In addition, the molar cont ent of total CYP in the cytoplasm was measured by microphotometry, and the expression of CYP2B2 mRNA was examined by in situ hybridization. When anima ls received the single injection, the isoforms and CYP2B2 mRNA increased ma rkedly in perivenular hepatocytes, increased somewhat in midzonal hepatocyt es, and remained unchanged in periportal hepatocytes. If animals received t he repetitive injections, however, although the isoforms and the mRNA incre ased markedly in perivenular hepatocytes, they also increased markedly in m idzonal hepatocytes and somewhat in periportal hepatocytes. These findings demonstrated that the enlargement of the sublobular area in which induction of the isoforms occurred was caused by the repetitive injections of PB the mselves. (C) 2000 Elsevier Science Inc.