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 tumours principally within the distal colon (Jackson et al., 1999. Carcinogenesis 20, 509-513). O(6)-Methylguanine (O(6)-MeG) levels, measured using a simple [3H]-based O(6)-alkylguanine-DNA alkyltransferase (ATase) inactivation assay, ranged from 0.6 to 16.7 fmol/microg 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/microg DNA within the colon but was not associated with adduct levels or tumour induction. After 6.8 mg/kg DMH, the half life of O(6)-MeG in colonic tissue was 36-42 h whereas after 68 mg/kg DMH, t1/2 was approximately 25, 57 and 96 h in the proximal, mid and distal colon, respectively. Tumour induction was thus associated with the levels and persistence of O(6)-MeG in the distal colon.
Jackson
P E
PE
CRC Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK.
Cooper
D P
DP
Meyer
T A
TA
Wood
M
M
Povey
A C
AC
Margison
G P
GP
D019813:1,2-Dimethylhydrazine / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D003106:Colon / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000032:analysis / Q000096:biosynthesis; D051379:Mice; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015203:Reproducibility of Results
D002273:Carcinogens; D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D019813:1,2-Dimethylhydrazine