Cellular basis for the loss of carcinogen from methylcholanthrene-impregnated Millipore membrane.

Millipore 'discs' impregnated with methylcholanthrene dissolved in wax or in crystalline form implanted subcutaneously in mice evoke an early intense macrophage and giant cell reaction; later the discs become covered with connective tissue, and eventually fibrosarcomas develop in their vicinity. Studies with tritium-labelled material show that under these conditions methylcholanthrene (MC) is removed from the discs and broken down rapidly (half life about 7 days) to a water-soluble product, which diffuses locally, is distributed widely via the blood stream, and is excreted in faeces and urine. Removal of label is halted by whole-body irradiation (550 R) with the disc area shielded; this observation, in conjunction with the histological and autoradiographic findings and the paucity of label in cells stripped from excised discs, points to the conclusion that the removal of MC from impregnated discs, and its subsequent degradation, depend on the presence of macrophages and the continual replacement of spent macrophages by new cells generated centrally. The rate of disappearance of label from implanted [3H]MC discs was not altered by administration of Corynebacterium parvum; this, however, does not exclude the possibility that the metabolic pathways involved in the removal of MC are altered. To investigate this it is proposed to study, in both normal mice and mice treated with C. parvum, the extent to which cytochrome P450 and other enzymes concerned in the activation and detoxification of polycyclic hydrocarbons by liver microsomal fractions are inducible in the macrophages that accumulate in inflammatory exudates. This histological techniques used should be readily applicable to the study of the early stages of chemical carcinogenesis and the host reaction to transformed cells.