Metabolism and biological effects of nitropyrene and related compounds

The aim of this project was to compare the carcinogenicities of 1,3-, 1,6-, and 1,8-dinitropyrene, 1-nitropyrene, and the metabolic phenolic derivatives of 1-nitropyrene. The biochemical goal was to establish how these inert compounds are converted metabolically, by target tissues, to reactive species that can alter the DNA of the susceptible cell. The comparative tumorigenicities were assessed by the use of female CD rats. Control groups consisted of animals that had been given only the solvent, dimethylsulfoxide, which has a low toxicity, to maximize solubility. Equimolar doses (1.7 mumole/ml; 10 mumole/kg body weight) of the compounds were administered to weanling rats by intraperitoneal injection, or by intragastric intubation, three times each week for four weeks, for a total dose of 16 mumoles. Newborn animals were treated by subcutaneous injection of the 1,3-, 1,6-, or 1,8-dinitropyrene or 1-nitropyrene within 24 hours of birth, and at seven weekly intervals, for a total dose of 6.3 mumoles. The possible carcinogenicities of phenolic metabolites of 1-nitropyrene were examined by subcutaneous treatment of newborn animals, and at seven weekly intervals, with 1-nitropyrene, 3-hydroxy-1-nitropyrene, or a mixture of 6-hydroxy-1-nitropyrene and 8-hydroxy-1-nitropyrene (70 mumoles/ml; 100 mumoles/kg body weight; total dose, 63 mumoles). The relative carcinogenicity of 1-nitropyrene in the female Fischer 344 rats was established by the concurrent treatment of appropriate animals. The smaller, inbred Fischer rats received a total dose of 40 mumoles. Subcutaneous and intraperitoneal treatments of weanling female CD rats (70 mumoles/ml; 100 mumoles/kg body weight; 5 weekly injections) with 1-nitropyrene were carried out to explore possible differences because of the different routes of administration in animals of the same age. Dinitropyrenes are much more carcinogenic than 1-nitropyrene (1,6- greater than 1,8- greater than 1,3-dinitropyrene greater than 1-nitropyrene). Phenolic derivatives of 1-nitropyrene are no more carcinogenic than the parent compound. The most likely tumors to be induced in this animal model are malignant fibrous histiocytomas (MFHs), mammary gland tumors, and leukemias. Animals treated with 1,6- or 1,8-dinitropyrene by subcutaneous injection yielded MFHs at the site within 15 weeks of the first injection (i.e., at 15 weeks of age), and this did not permit them to survive more than 20 to 25 weeks. Leukemia developed in these animals within this brief period, but mammary gland tumors were observed only when survival of the animal was not limited by the formation of the more aggressive MFHs.(ABSTRACT TRUNCATED AT 400 WORDS)