DNA alkylation and mutagenicity of related hydroxypropylating and methylating agents in V79 cells.
N-Nitrosobis (2-hydroxypropyl) amine (BHP) and N-nitrosobis (2-oxopropyl) amine (BOP) require metabolism to be carcinogenic and mutagenic. This metabolism produces hydroxypropylating and methylating alkylating species. To measure the effects of these species, we compared the action of direct-acting model compounds that are hydroxypropylating or methylating agents with those of BHP and BOP. Mutagenicity in V79 cells and the alkylation of V79 cell DNA were measured. The model compounds were ethyl-N-nitroso (2-oxopropyl) carbamate (NOPC), a methylating agent, and its 2-hydroxypropyl congener (NHPC), a hydroxypropylating agent. BHP and BOP were metabolized by hepatocytes from male Syrian hamsters. At the highest dose (2 mM) BOP produced 12 times more mutants than BHP but only 2.5 times more O6 methylguanine (O6MeG) than BHP. When a pancreas duct homogenate was used, 87 (BOP) and six (BHP) mutants/10(6) survivors were measured. When hepatocytes (not a homogenate) were used to metabolize BOP, 351 mumol O6MeG/mol guanine (G) and 39 mumol O6 (2-hydroxypropyl) G (O6HpG)/mole G were found in V79 DNA. When a pancreas duct homogenate was used BHP produced O6HpG (65 mumol/mol G) and BOP O6MeG (20 mumol/mol G). NOPC produced five times more mutants than NHPC, over the range of doses. At the highest dose (10 microM) it produced less (70%) O6alkylG than NHPC. These data show that methylation was a more mutagenic lesion than hydroxypropylation. There was no evidence of a correlation between mutagenicity and the formation of O6alkylG.
Lawson
T
T
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198-6805.
Gannett
P
P
D000477:Alkylating Agents / Q000633:toxicity*; D000478:Alkylation; D000818:Animals; D002219:Carbamates / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D006224:Cricetinae; D004249:DNA Damage; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009602:Nitrosamines / Q000633:toxicity; D010179:Pancreas / Q000166:cytology / Q000378:metabolism
D000477:Alkylating Agents; D002219:Carbamates; D002273:Carcinogens; D009153:Mutagens; D009602:Nitrosamines; C012457:diisopropanolnitrosamine; C013622:nitrosobis(2-oxopropyl)amine