Non-enzymatic extramicrosomal bioactivation of chemical carcinogens by phagocytes: A proposed new pathway

Abstract

A theory of bioactivation of precarcinogens is presented whose new features are the following: (1) it proposes a non-enzymatic pathway for bioactivation, (2) it explains the role of inert substances in carcinogenesis, (3) it explains the synergism between inert substances and chemical carcinogens in the genesis of neoplasms and (4) it explains the role of inflammation in carcinogenesis. The theory proposes that during the attempted phagocytosis of fibrous minerals, selected foreign bodies and analogous substances, production of reactive oxygen products takes place. These products are released from phagocytic cells, and can have several fates: (1) they can react with each other to yield even more strongly reactive species, (2) they can react with unsaturated molecules yielding mutagenic substances or (3) they can do both. When such species interact either with polynuclear aromatic hydrocarbons or unsaturated fatty acids, products capable of initiating a neoplastic transformation are formed. In this manner we explain, for example, the synergism between cigarette smoking and asbestos in causing a high incidence of cancer of the lung among exposed subjects. This particular example is prototypic for the whole field of “foreign body” or “solid state” carcinogenesis. That extramicrosomal bioactivation does occur in the biological setting is proposed here as complementary to the classical mono-oxygenases-mediated bioactivation processes.