7-methylguanine and Precancerous-Conditions

Methylazoxymethanol (MAM) and its chemical and metabolic precursor, azoxymethane (AOM), both strong colon carcinogens in rodents, can be metabolically activated by CYP2E1 in vitro. Using CYP2E1-null mice, we found that CYP2E1 deficiency differentially affects the activation of AOM and MAM, as reflected in DNA guanine alkylation in the colon and in the formation of colonic aberrant crypt foci (ACF). Male and female inbred 129/SV wild-type (WT) and CYP2E1-null (null) mice were treated with 189 micromol/kg of either AOM or methylazoxymethyl acetate (MAMAc), and 7-methylguanine (7-MeG) and O(6)-methylguanine (O(6)-MeG) were measured in the DNAs of various organs. The levels of O(6)-MeG (as pmol/nmol guanine) in the liver, colon, kidney, and lung of male null mice treated with AOM were 87, 48, 70, and 43% lower, respectively, than in AOM-treated WT mice. In null mice treated with MAMAc, the DNA O(6)-MeG levels were lower by 38% in the liver but were higher by 368, 146, and 194% in the colon, kidney, and lung, respectively, compared with the same organs of WT mice treated in the same way. Determination of ACF revealed that although AOM-induced ACF formation was significantly lower in the null group than in the WT group, MAMAc-induced ACF formation was significantly higher in the null group than in the WT group. These results demonstrate an important role for CYP2E1 in the in vivo activation of AOM and MAM and suggest that agents that modify CYP2E1 activity at the tumor initiation stage might either enhance or inhibit colon carcinogenesis, depending on whether AOM or MAMAc is used as the carcinogen. The mechanism of this effect is discussed.

Topics: Animals; Azoxymethane; Biotransformation; Carcinogens; Colon; Cytochrome P-450 CYP2E1; DNA; DNA Methylation; Female; Guanine; Liver; Male; Methylazoxymethanol Acetate; Mice; Precancerous Conditions

Nitrosodimethylamine (NDMA) at 26 mumol/kg, and nitrosomethylbenzylamine (NMBzA) at 33.5 mumol/kg were equally potent in producing 7-methylguanine and O6-methylguanine in rat liver DNA. These doses were used to compare the abilities of the two nitrosamines to initiate production of putative preneoplastic foci in rat liver. Whereas NMBzA resulted in no increase above the background level of foci (0.9 +/- 0.1 foci/cm2), NDMA produced 7.5 +/- 0.6 foci/cm2. Co-administration of NDMA and NMBzA produced no more foci than NDMA alone, even though the combined effect of the two nitrosamines on DNA methylation was additive. The results suggest that methylation of hepatic DNA by nitrosamines does not predict initiation of preneoplastic foci.

Topics: Animals; Dimethylnitrosamine; DNA; Dose-Response Relationship, Drug; Guanine; Liver; Liver Neoplasms, Experimental; Male; Methylation; Precancerous Conditions; Rats; Rats, Inbred Strains