Dietary butylated hydroxytoluene protects cytochrome P-450 in hepatic nuclear membranes of rats fed 2-acetylaminofluorene.

We previously reported that during hepatocarcinogenesis which is induced by feeding 2-acetylaminofluorene (AAF) there is an early loss of cytochrome P-450 in the nuclear envelope (Carubelli et al., Chem. Biol. Interact. 58, 125-136, 1986). Cytochrome P-450 participates in the activation in addition to the detoxification of xenobiotics; therefore, these findings suggested that AAF may cause the loss of an important defense for the protection of the genetic material of the nucleus against carcinogenic metabolites of AAF generated by microsomal P-450 which, in contrast to the nuclear envelope cytochrome P-450, remains essentially undiminished during early stages of AAF feeding. Because dietary butylated hydroxytoluene (BHT) affords good protection against AAF carcinogenicity, we decided to investigate the possibility that the BHT effect could be mediated through the preservation of nuclear envelope cytochrome P-450. AAF (0.05% wt/wt) was administered in a purified diet with a high content of polyunsaturated fat (20% wt/wt corn oil), which is known to enhance AAF carcinogenicity. These studies showed that BHT supplementation (0.3% wt/wt) of control in addition to the AAF-containing diets resulted in higher levels of nuclear envelope cytochrome P-450. After 16 weeks of AAF feeding, nuclear envelope cytochrome P-450 could not be detected in rats fed BHT-free diet, whereas in the rats fed the diet containing AAF and BHT, measurable amounts of nuclear envelope P-450 were observed. These results are compatible with the hypothesis that nuclear envelope cytochrome P-450 is needed for protection against AAF and that BHT protects nuclear envelope cytochrome P-450.