Formation and persistence of O-6-methylguanine in the mouse colon following treatment with 1, 2-dimethylhydrazine as measured by an O-6-alkylguanine-DNA alkyltransferase inactivation assay

Female SWR mice were treated with 1,2-dimethylhydrazine (DMH: 6.8 mg/kg i.p . injection) once weekly for up to 10 weeks, a dosing regime that produced rumours principally within the distal colon (Jackson et al., 1999. Carcinog enesis 20, 509-513). O-6-Methylguanine (O-6-MeG) levels, measured using a s imple [H-3]-based O-6-alkylgua nine-DNA alkyltransferase (ATase) inactivati on assay, ranged from 0.6 to 16.7 fmol/mu g DNA with: (i) highest levels in the distal colon; and (ii) higher levels after 68 mg/kg total DMH than 6.8 mg/kg DMH. Basal ATase activity varied between 0.97 and 1.22 fmol/mu g DNA within the colon but was not associated with adduct levels or tumour induc tion. After 6.8 mg/kg DMH, the half life of O-6-MeG in colonic tissue was 3 6-42 h whereas after 68 mg/kg DMH, t1/2 was approximately 25, 57 and 96 h i n the proximal, mid and distal colon, respectively. Tumour induction was th us associated with the levels and persistence of O-6-MeG in the distal colo n. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.