SPECIES DIFFERENCES IN THE INDUCTION OF MICROSOMAL HEMOPROTEINS AND 3,4-BENZPYRENE HYDROXYLASE BY PHENOBARBITAL AND 3-METHYLCHOLANTHRENE

¹ The Weilcome Research Laboratories, Burroughs Weilcome and Company (U.S.A.) Inc., Tuckahoe, New York

The effect of phenobarbital and 3-methylcholanthrene (3-MC) on the spectral properties of cytochrome P-450 and on the activity of 3,4-benzpyrene (BP) hydroxylase has been investigated in rats, mice, guinea pigs and rabbits. Phenobarbital treatment caused a 3-fold increase in BP hydroxylase in mice, guinea pigs and rabbits and only 50% increase in rats. 3-MC treatment resulted in no significant increase in BP hydroxylase in rabbits, a 2-fold increase in mice and guinea pigs and a 4- to 5-fold increase in rats. In all phenobarbital-treated animals, the wavelengths of maximum absorption of the hemoprotein-CO complex were similar to those observed in untreated animals. In contrast, after 3-MC administration, a peak shift occurs towards shorter wavelengths in the absorption maximum of the CO complex of the induced hemoprotein. Similar peak shifts towards shorter wavelengths were seen in the oxidized spectra of P-450 and in the 455-mµ peak of the ethyl isocyanide complex of the 3-MC-induced hemoprotein. In rats, 3-MC treatment resulted in peak shifts, changes in the ratio of the 455:430-mµ peaks of the ethyl isocyanide difference spectrum and a change in the K_m for BP hydroxylation. However, in other species studied, after 3-MC treatment, no correlation between peak shifts in the CO-hemoprotein complex spectra and changes in the ratio of the ethyl isocyanide difference spectra peaks and kinetics of BP hydroxylation was observed. These results suggest that species variations in the inducibiity of microsomal drug metabolism may be due to qualitative, as well as quantitative differences in the rate-limiting components of the hydroxylase system.