Modulation of O6-methylguanine-DNA methyltransferase in rat and hamster liver after treatment with dimethylnitrosamine.
Distinct species differences exist between BDIV rats and Syrian Golden hamsters in the repair of methylated DNA lesions, after single exposures to dimethylnitrosamine (DMN). The promutagenic lesions O6-methylguanine (O6-MeG) and O4-methylthymidine were actively repaired in rat liver; in contrast, in hamster liver the levels of O6-MeG remained relatively stable while O4-methylthymidine levels were reduced. Species differences in the levels of two enzymes involved in the repair of DNA alkylation damage were also noted. An increase in the methylpurine-DNA glycosylase levels was seen in both species following DMN exposure; however, significant species differences in the inactivation and subsequent time course of recovery of the "suicide protein" O6-MeG-DNA methyltransferase were observed. In the rat a rapid recovery of activity began within 24 h of DMN exposure (20 mg/kg) and an approximately 3-fold induction in enzyme levels was observed at 96 h. In hamster liver, in which the constitutive level of expression of this enzyme is similar, no activity was detectable up to 96 h after treatment (25 mg/kg DMN). Only in animals in the lowest treatment group (2.5 mg/kg DMN) was a significant recovery seen, 264 h after treatment. The data presented suggest that the schedule of DMN treatment, in particular the time between doses of the carcinogen and the regeneration of the O6-MeG-DNA methyltransferase, would evoke different carcinogenic responses in hamster and rat liver following chronic exposure to alkylating agents.
Hall
J
J
Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Brésil
H
H
Serres
M
M
Martel-Planche
G
G
Wild
C P
CP
Montesano
R
R
D000818:Animals; D006224:Cricetinae; D004247:DNA / Q000302:isolation & purification; D004128:Dimethylnitrosamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D008780:Methyltransferases / Q000378:metabolism*; D009336:Necrosis; D019853:O(6)-Methylguanine-DNA Methyltransferase; D051381:Rats; D011919:Rats, Inbred Strains; D013936:Thymidine / Q000031:analogs & derivatives / Q000032:analysis
C008505:O-methylthymidine; D004247:DNA; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D004128:Dimethylnitrosamine; D013936:Thymidine