Pathobiologic and metabolic aspects of mammary gland tumorigenesis by N-substituted aryl compounds.

Metabolic or synthetic N-hydroxylation of N-arylamides yields N-arylacylhydroxamic acids considerably more carcinogenic for the rat mammary gland than the parent amides both by systemic and topical administration. The size of the aryl moiety, the position of the nitrogen relative to the aryl moiety and the type of acyl group are determinants of the carcinogenic potency of N-arylacylhydroxamic acids. Induction of mammary tumors required ovarian hormones. Receptors for estrogen, androgen and progesterone were shown in the N-hydroxy-N-2-fluorenylacetamide (N-OH-2-FAA)-induced mammary carcinoma. This tumor involved epithelial and stromal components of the mammary gland that were separated in culture and produced tumors of their respective origin in the isologous host. Both mammary epithelial cells and fibroblasts are capable of metabolism of carcinogens. The enzymes potentially involved in metabolic activation of N-arylamides and N-arylacylhydroxamic acids in the mammary gland include: a cytochrome P-450(P(1)-450) system, UDP-glucuronyltransferase, N,O-acyltransferases and peroxidases. Mammary microsomes in which cytochrome P(1)-450 was induced generated small amounts of N-OH-2-FAA from 2-FAA. N-OH-2-FAA and its carcinogenic isomer, N-OH-3-FAA, were oxidized by cytochrome c/H(2)O(2) to the nitroxyl free radicals which dismutated to the respective acetate esters and nitrosofluorenes. The addition of unsaturated lipid to either the free radicals or to the nitrosofluorenes gave electron spin resonance signals characteristic of immobilized radicals. It is proposed that interactions of carcinogens with lipids and with DNA play a role in mammary tumorigenesis.