The role of microsomes and nuclear envelope in the metabolic activation of benzo(a)pyrene leading to binding with nuclear macromolecules.

In an attempt to resolve existing conflicting reports and further substantiate the roles of microsomes and the nuclear envelope in the metabolic activation of benzo(a)pyrene (BP), factors affecting the binding of BP to the DNA, RNA, histone, and nonhistone proteins of isolated nuclei were investigated. Examination of the spectra and catalytic properties of the mixed-function oxidase systems of nuclei and microsomes indicated that they are similar. Regard less of the BP concentration used, microsomes from control or 3-methylcholanthrene-treated rats increased the binding of BP to the components of control nuclei. With 30 IJLMBP, microsomes enhanced the binding to the nuclei from 3-methylcholanthrene-treated rats. With lower BP con centrations (1 to 2 /J.M),addition of microsomes reduced the binding. A reduction was also observed when denatured microsomes were added. It was shown that the reduction was due to physical binding rather than the metabolism of BP by microsomes, and in fact the latter contributed to the binding of BP to nuclear components. With incubation sys tems containing microsomes and nuclei, the results indi cated that microsomes can (a) activate BP leading to bind ing with nuclear macromolecules; and (o) physically bind BP and reduce the effective BP concentration around the nuclei. Both the microsomes and nuclear envelope are po tentially important in the activation of carcinogens. The endoplasmic reticulum may play a more important role than the nuclei in the activation of BP when the carcinogen is present in high concentrations. When the concentration of the carcinogen is low, the endoplasmic reticulum should still contribute to the metabolic activation of BP, although it would also physically bind BP and lower the concentration of BP available for nuclear metabolism.