Cytochrome P450 in the breast and brain: Role in tissue-specific activation of xenobiotics

It is still an open question as to whether, upon administration of procarcinogens to rodents, development of cancers in extrahepatic tissues is due to activation of these chemicals in the liver or to in situ activation within the tissue. The low level of P450 in many tissues means that it is very difficult to demonstrate the formation of significant amounts of reactive metabolites when these tissues are incubated with procarcinogens in vitro. It is our contention that the importance of tissue-specific activation of procarcinogens can best be decided when the cells which harbour P450 have been identified and the isozyme profile in the cells defined. With this aim in view, we have begun to characterize the forms of P450 in the breast and brain. Perhaps not surprisingly, the P450s in the breast are regulated as a function of age and hormonal status of rats and most of the breast P450 can be accounted for by hepatic forms. The P450 content of the brain, on the other hand, is very responsive to environmental factors. The quantity of P450 as well as the isozyme profile is altered by drugs and chemicals in the environment. The P450s induced in the brain are similar to liver P450s, but the constitutive forms are not. P450s of the 1A family are inducible in both tissues and this indicates that heterocyclic amines can be activated in the brain and polycyclic aromatic hydrocarbons in the breast. The cells in which this activation can occur remain to be identified.