Selective induction and inhibition of the components of 7-ethoxycoumarin O-deethylase activity in the rat

Abstract

1. Treatment of rats with 3-methylcholanthrene increased V_max of the high-affinity component of 7-ethoxycoumarin O-deethylase activity 60-fold. There was also an increase in V_max of the low-affinity component.

2. Treatment with phenobarbitone increased V_max of the high-affinity component sixfold whilst not affecting the K_m of this component. Modest changes were also observed in the kinetics of the low-affinity component.

3. Following treatment with 3-methylcholanthrene, the sensitivity of both the high- and low-affinity components of activity to inhibition by α-naphthoflavone was considerably increased, with the IC₅₀ decreasing from >250μM to < 10 μM in both instances.

4. Following treatment with phenobarbitone, the sensitivity of the low-affinity component to inhibition by metyrapone was considerably increased, with the IC₅₀ decreasing from > 1000 μM to 96 μM. There was also a modest, but significant, increase in sensitivity of the high-affinity component to metyrapone.

5. These results indicate that both components of 7-ethoxycoumarin O-deethylase activity are catalysed by more than one form of cytochrome P-450.