COMPARATIVE ELECTROPHILICITY, MUTAGENICITY, DNA-REPAIR INDUCTION ACTIVITY, AND CARCINOGENICITY OF SOME N-ACYL AND O-ACYL DERIVATIVES OF N-HYDROXY-2-AMINOFLUORENE

Abstract

N-Myristoyloxy-N-acetyl-2-aminofluorene, N-acetoxy-N-myristoyl-2-aminofluorene, N-myristoyloxy-N-myristoyl-2-aminofluorene and N-hydroxy-N-myristoyl-2-aminofluorene each yielded a high incidence of sarcomas in male rats within 5-7 mo. after s.c. injection of 64 .mu.mol in divided doses. N-Acetoxy-N-acetyl-2-aminofluorene and N-hydroxy-2-acetylaminofluorene, although potent carcinogens at the s.c. site, were less active than the above derivatives with a myristoyl substituent. N-Sulfonoxy-N-acetyl-2-aminofluorene (purity .gtoreq. 70%) had little or no carcinogenic activity when administered in large amounts by s.c. injection to rats. The low incidence of tumors could have resulted from N-hydroxy-2-acetyllaminofluorene or other decomposition products of the N-sulfonoxy derivative. Each of the N-aetoxy and N-myristoyloxy derivatives of N-acetyl-2-aminofluorene and of N-myristoyl-2-aminofluorene showed electrophilic activity toward methionine; N-acetoxy-N-acetyl-2-aminofluorene was the most reactive and N-myristoyloxy-N-myristoyl-2-aminofluorene was the least reactive. Each of these esters also induced unscheduled 3H-thymidine incorporation in nondividing cultured human fibroblasts and appeared to induce lesions in DNA that lead to repair synthesis. Each of the N-acetoxy derivatives was mutagenic for Salmonella typhimurium strains TA98 and TA1538 without tissue activation. Neither N-myristoyloxy derivative was mutagenic under these conditions. While there was a qualitative correspondence between several of the above activities of these 2-aminofluorene derivatives, the quantitative differences and the lack of detectable mutagenicity of the 2N-myristoyloxy derivatives for S. typhimurium indicate the need for mutiple short-term tests in the qualitative prediction of potential carcinogenic activity.