Phenobarbital: a non-genotoxic agent which induces the repair of O6-methylguanine from hepatic DNA

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Abstract
Exposure to phenobarbital (PB) (0.05% in drinking water) markedly increased the rate of repair of O6methylguanine (O6-MeG) from the hepatic DNA of rats given N-nitrosodi-methylamine (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 ∼ 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. Immunohistichemical 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 (Evars 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.

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