title: Local carcinogenicity, rates of absorption, extent and persistence of macromolecular binding, and acute histopathological effects of N-hydroxy-1-naphthylamine and N-hydroxy-2-naphthylamine.
abstract: The N-hydroxy derivatives of 1- and 2-naphthylamine (NA) are directly carcinogenic at sites of application. In this study, the carcinogenicity of these two compounds at s.c. injection sites was compared with their relative rates of absorption, with the extent and persistence of their binding to protein, RNA, and DNA in the skin-subcutis, and with acute histopathological changes observed after local application. Male Sprague-Dawley rats were given injections of the N-hydroxy derivatives in the right rear leg at 16 mumol/dose. When administered twice weekly for 12 weeks, N-hydroxy-1-NA caused a 100% incidence (30 of 30) of poorly differentiated sarcomas at the injection site. N-Hydroxy-2-NA administered in a similar manner resulted in a low yield of tumors (7%; 2 of 30). Injection of N-hydroxy-1-NA once weekly for 12 weeks or twice weekly for 6 weeks also induced a high incidence of sarcomas (93 to 97%), but the time to tumor formation was significantly longer (p less than 0.0001) than in animals treated twice weekly for 12 weeks. The tumors were classified as malignant fibrous histiocytomas. Possible antagonistic or synergistic effects between the two compounds were also investigated. A sequential 6-week treatment with each of the N-hydroxy derivatives did not alter the expected tumor yields. However, alternating injections over 12 weeks caused a significant lengthening in the time to tumor formation (p less than 0.05). N-Hydroxy-1-NA bound covalently to protein, RNA, and DNA to a much greater extent than did N-hydroxy-2-NA. Protein binding with both derivatives decreased by 80 to 90% by 7 days after treatment. RNA binding in N-hydroxy-1-NA-treated rats markedly decreased, while N-hydroxy-2-NA-bound residues diminished only slightly. During this period, the extent of DNA binding with both derivatives remained fairly constant. When N-hydroxy-2-NA was injected 3 days after N-hydroxy-1-NA, there was a marked reduction in the apparent levels of N-hydroxy-1-NA bound to RNA and DNA. The greater tumorigenicity of N-hydroxy-1-NA versus N-hydroxy-2-NA correlated with its greater extent of macromolecular binding. Examination of acute histopathological changes occurring after single injections of N-hydroxy-1-NA and/or N-hydroxy-2-NA indicated that both compounds caused extensive necrosis in tissues at the injection site.(ABSTRACT TRUNCATED AT 400 WORDS)
mesh_terms: D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004347:Drug Interactions; D007700:Kinetics; D008297:Male; D009281:Naphthalenes / Q000633:toxicity*; D009336:Necrosis; D051381:Rats; D011919:Rats, Inbred Strains; D012509:Sarcoma / Q000139:chemically induced* / Q000473:pathology; D012867:Skin / Q000473:pathology; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: D002273:Carcinogens; D009281:Naphthalenes; D014316:Tritium; C017893:N-hydroxy-1-naphthylamine; D015057:1-Naphthylamine; D015081:2-Naphthylamine; C019424:N-hydroxy-2-naphthylamine