DNA ALKYLATION AND MUTAGENICITY OF RELATED HYDROXYPROPYLATING AND METHYLATING AGENTS IN V79 CELLS

N-Nitrosobis (2-hydroxypropyl) amine (BHP) and N-nitrosobis (2-oxoprop yl) amine (BOP) require metabolism to be carcinogenic and mutagenic. T his metabolism produces hydroxypropylating and methylating alkylating species. To measure the effects of these species, we compared the acti on of direct-acting model compounds that are hydroxypropylating or met hylating agents with those of BHP and B OF. 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 age nt, and its 2-hydroxypropyl congener (NHPC), a hydroxypropylating agen t. BHP and BOP were metabolized by hepatocytes from male Syrian hamste rs. At the highest dose (2 mM) BOP produced 12 times more mutants than BHP but only 2.5 times more O-6 methylguanine (O(6)MeG) than BHP. Whe n a pancreas duct homogenate was used, 87 (BOP) and six (BHP) mutants/ 10(6) survivors were measured. When hepatocytes (not a homogenate) wer e used to metabolize BOP, 351 mu mol O(6)MeG/mol guanine (G) and 39 mu mol O-6 (2-hydroxypropyl) G (O(6)HpG)/mole G were found in V79 DNA. W hen a pancreas duct homogenate was used BHP produced O(6)HpG (65 mu mo l/mol G) and BOP O(6)MeG (20 mu mol/mol G). NOPC produced five times m ore mutants than NHPC, over the range of doses. At the highest dose (1 0 mu M) it produced less (70%) O(6)alkylG than NHPC. These data show t hat methylation was a more mutagenic lesion than hydroxypropylation. T here was no evidence of a correlation between mutagenicity and the for mation of O(6)alkylG. (C) 1993 Wiley-Liss, Inc.