Phenobarbital: a Non-genotoxic Agent Which Induces the Repair of O6-methylguanine from Hepatic DNA

Exposure to phenobarbital (PB) (0.05% in drinking water) markedly increased the rate of repair of O6-methylguanine (O6-MeG) from the hepatic DNA of rats given N-nitrosodimethylamine (2 mg/kg). No effect of comparable magnitude was seen for the repair of O4-methylthymine. During 21 weeks of exposure to PB the increased repair of O6-MeG exhibited a biphasic response and was maximal at approximately 3 weeks of treatment. Although this increased repair was readily observed when direct measurements were made of the loss of O6-MeG from hepatic DNA in vivo, no corresponding increased level of methyltransferase activity was detected in cell-free liver extracts, indicating that the methyltransferase protein was induced in a relatively limited population of cells. Immunohistochemical procedures have been used to demonstrate the formation of O6-MeG in, and its repair from, the DNA of hepatocytes in the centrilobular region of the liver lobule. Comparison with published data, for changes in the level of asialoglycoprotein receptors [Evarts et al. (1985) Carcinogenesis, 6, 1767-1773] and for the induction of cytochrome P450 [Schwartz et al. (1987) Carcinogenesis, 8, 1355-1357] in hepatocytes during PB administration, indicate that PB is acting at membrane sites in a relatively limited population of cells associated with the central vein. These observations show that the methyltransferase activity responsible for the repair of the major promutagenic base O6-MeG can be induced by a membrane active agent, without recourse to the genotoxic action of initiators and toxins, or the induction of restorative hyperplasia, previously employed for this purpose.