We have generated mice deficient in O6-methylguanine DNA methyltransferase activity encoded by the murine Mgmt gene using homologous recombination to delete the region encoding the Mgmt active site cysteine. Tissues from Mgmt null mice displayed very low O6-methylguanine DNA methyltransferase activity, suggesting that Mgmt constitutes the major, if not the only, O6-methylguanine DNA methyltrans...

The tumorigenic activities and DNA methylating abilities in F344 rats of the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and the structurally related nitrosamine A/-nitrosodimethylamine (NDMA) were compared. Groups of 30 male rats were given 60 s.c. injections of 0.0055 mmol/kg of either NNK or NDMA over a 20-week period (total dose, 0.33 mmol/kg). The expe...

It was found that rat kidney contains a protein similar to that previously described in rat liver which catalyzes the transfer of the methyl group from O6-methylguanine in DNA to a protein-bound cysteine residue. The amount of the renal O6-methylguanine-DNA methyltransferase was increased up to 2.5-fold during renal hypertrophy in response to unilateral nephrectomy or treatment with folic acid....

O6-Methylguanine has been measured in peripheral blood leukocytes of 14 patients during one or more cycles of treatment with procarbazine (daily treatment for 10 days) and in 12 patients during one or more cycles of treatment with dacarbazine (single dose per cycle). Adduct formation at levels up to about 0.4 fmole/microgram DNA was detected in all procarbazine- and all but one dacarbazine-trea...

4-(A/-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major nitrosamine formed in tobacco smoke, induces a high incidence of lung, liver, and nasal cavity tumors in rats. Since «hydroxylation of NNK by target tissues can lead to the generation of a methylating agent, the formation and removal of 7-methylguanine and the promutagenic lesions O6-methylguanine (O6mGua) and 0"-methyldeoxyth...

Mammary and skin tumors induced in rodents by ¿Y-methyl-/V-nitrosourea treatment have a (.:( to A: I transition mutation in codon 12 of I I-/Õ/.Y, probably resulting from alkylation of <>" of guanine by the carcinogen. This codon contains two guanines (5'-GGA-3'), but mutations are observed only in the central base pair of this codon. The same selectivity for mutations of -GGA-sequences has a...

Methylating agents are first-line therapeutics for gliomas and malignant melanomas. They attack DNA at various sites, and both O(6)-methylguanine and N-methylated base adducts contribute to the killing response. The mechanism of cellular defense against these agents primarily involves O(6)-methylguanine-DNA methyltransferase (MGMT) and base excision repair (BER). Here, we determined whether a k...

The AlkB enzyme is an Fe(II)- and α-ketoglutarate-dependent dioxygenase that repairs DNA alkyl lesions by a direct reversal of damage mechanism as part of the adaptive response in E. coli. The reported substrate scope of AlkB includes simple DNA alkyl adducts, such as 1-methyladenine, 3-methylcytosine, 3-ethylcytosine, 1-methylguanine, 3-methylthymine, and N(6)-methyladenine, as well as more co...

Ellagic acid, a naturally occurring plant phenol, inhibits the activity of the direct-acting mutagen N-methyl-N-nitrosourea (MeNU) in Salmonella typhimurium TA100. Ellagic acid at 0.10, 0.25, 0.50, and 1.00 mM inhibited the mutagenicity of MeNU (0.40 mM) by 3%, 13%, 45%, and 60%, respectively. Ellagic acid (3 mM) also inhibited the mutagenic activity of N,N-dimethylnitrosamine (25-200 mM) in th...

The methylation by 3,3-[~4C]dimethyl-l-phenyltriazene of nucleic acids in various rat tissues was investigated. Following a single s.c. injection of 3,3-['4C]dimethyl-l-phenyl triazene (50 mg/kg), approximately 40% of the radioactivity was subsequently exhaled as ~4CO2. Expiration of '4CO2, metabolic ]4C labeling of liver proteins, and formation of 7[~4C]methylguanine, the major reaction produc...