The excretion of 7-methyladenine in the urine of rats exposed to carcinogenic methylating agents.
Earlier studies showed that urine of rats which had been injected with the methylating agent N-[3H-methyl]-N-nitrosourea contained a previously undetected metabolic product, 7-[3H-methyl]adenine. This methylpurine, undoubtedly derived from alkylation of nucleic acids followed by depurination, was not labeled when 14C-methyl-labeled methionine was administered concurrently. To establish whether urinary 7-methyladenine (7-MA) might serve as a marker of exposure to exogenous and carcinogenic methylating agents, the excretion of 7-MA following injection of methylating agents was measured. A GC-MS method, using pentafluorobenzyl derivatives and an internal standard of tri-deutero-7-MA, was developed to assay levels of 7-MA. Increasing the i.p. dose of N-methylnitrosourea (MNU) from 2 to 80 mg/kg/rat resulted in a linear increase in urinary 7-MA, which at the highest dose was 1.6 micrograms during the first day and another 0.4 microgram during day 2. Doses of 5 mg/kg MNU led to elevated urinary levels of 7-MA (144 ng) compared to controls (26 ng). Other methylating agents, such as dimethylnitrosamine, N-methyl-N'-nitro-N-nitrosoguanidine and dimethyl sulfate, also provided urinary 7-MA. To determine the fate of injected 7-MA, the administration of 2 micrograms 7-[3H-methyl]adenine led to an 80% recovery of radioactivity in the urine, almost all of it during the first 24 h. No other labeled metabolites were detected. At least for the rat, urinary 7-MA serves as an indicator of exposure to methylating agents.
Mandel
H G
HG
Department of Pharmacology, George Washington University Medical Center, Washington, DC 20037.
Straw
J A
JA
Wenger
L J
LJ
Kusmierz
J J
JJ
D000225:Adenine / Q000031:analogs & derivatives* / Q000652:urine; D016604:Aflatoxin B1 / Q000378:metabolism; D000477:Alkylating Agents / Q000378:metabolism*; D000818:Animals; D004128:Dimethylnitrosamine / Q000378:metabolism; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000378:metabolism; D008770:Methylnitrosourea / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D000477:Alkylating Agents; D008769:Methylnitronitrosoguanidine; D008770:Methylnitrosourea; C059225:7-methyladenine; D016604:Aflatoxin B1; D000225:Adenine; D004128:Dimethylnitrosamine