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.
O'Connor
P J
PJ
CRC Section of Carcinogenesis, Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, UK.
Fida
S
S
Fan
C Y
CY
Bromley
M
M
Saffhill
R
R
D015073:2-Acetylaminofluorene / Q000494:pharmacology; D000818:Animals; D004260:DNA Repair / Q000187:drug effects*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D008099:Liver / Q000502:physiology*; D008780:Methyltransferases / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D013941:Thymine / Q000031:analogs & derivatives / Q000378:metabolism
C021223:O-4-methylthymine; D006147:Guanine; C008449:O-(6)-methylguanine; D015073:2-Acetylaminofluorene; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013941:Thymine; D010634:Phenobarbital