Induction of Cytochrome P450 1A1 in Mice by Repeated Oral Administration of Propranolol

Abstract

Pretreatment of adult male C57BL/6 mice with propranolol (PL, 100 mg/kg, p.o., once a day for five days) significantly increased PL N-deisopropylase activity and decreased PL 7-hydroxylase activity in liver microsomes, whereas PL 4- and 5-hydroxylase activities remained unchanged. In the present study, we have examined the mechanism for the elevation of the oxidation of PL side chain. Immunoblot analysis using polyclonal antibodies raised against rat liver CYP enzymes such as CYP1A1, -2B2, -2C11, -2D2, -2E1 and 3A2 showed that, compared with the vehicle-treated control, the levels of two protein bands (54 KD and 52 KD) were increased by the pretreatment. Both proteins immunochemically cross-reacted with the antibodies against rat CYP1A1, and from their molecular weights, the 54 KD and 52 KD proteins were deduced to be CYP1A1 and 1A2, respectively. Computer-assisted scanning analysis revealed that the levels of CYP1A1 and CYP1A2 proteins were increased 1.8 and 1.2 times, respectively, over those of control microsomes. PL N-deisopropylase activity correlated well with ethoxyresorufin O-deethylase (r=0.828) and phenacetin O-deethylase (r=0.851) activities in the same microsomal fractions. These results show that repeated oral administration of PL in mice induces mainly CYP1A1 and also CYP1A2 to some extent, which contrasts from our previous results in rats in which CYP1A2 only was induced with PL pretreatment [Narimatsu et al., Chemico-Biol. Interact., 101, 207-224 (1996)].