1995 Volume 10 Issue supplement Pages 146-149
We examined the mechanisims of inhibition andelelvation of CYP enzyme activities in liver microsomes (Ms) from propranolol (PL)-pretreated rats. In the studies on the inhibition, we measured radioactivities derived from side chain-[14C]-labeled and aromatic ring-[14C]-labeled 4-hydroxypropranolols (4-OH-PL) after incubation with Ms and NADPH. Radioactivities were significantly higher in aromatic ring-labeled 4-OH-PL than in side chain-labeled one. A strain difference was observed in radioactivities derived from the aromatic ring-labeled 4-OH-PL(Wistar>DA), but not in those from the side chain-labeled one. We speculated that CYP2D enzymes converted PL to 4-OH-PL, which was then converted to 1, 4-naphthoquinone (1, 4-NO), causing the enzyme inhibition by covalently binding to apoprotein. However, 1, 4-NQ or 1, 4-dihydroxynaphthalene, when added to the incubation medium containing Ms and NADPH, did not inhibit CYP2D activities. The results suggest that some other metabolite(s) together with 1, 4-NQ could contribute to the enzyme inhibition. In the studies on the elevation of enzyme activities, we observed that elevated PL N-desisopropylase activity highly correlated with O-deethylase activities of phenacetin (PA) and ethoxyresorufin (ER) in liver microsomes from PL-pretreated rats. After repeated administrations of PLrecemate and enantiomers to rats, the potencies in elevation of CYP1A1 protein and activities (ER oxidation and PL N-desalkylation) were RS>S>R, whereas those in elevation of CYPIA2 protein and activities (PA oxidation and PLN-desalkylation) were RS>R>S. In the primary culture system of rat hepatocytes, potencies in elevation of CYP1A1 protein and the activities were R>RS>S, and no effect was observed from CYP1A2. These results indicate that elevation of PLN-desisopropylase activities could be caused by induction of CYPIA enzyme by repeated administration of PL.
