The effect of tryptophan on the phenobarbital-mediated induction of cytochrome P-450 in rat liver. The role of tryptophan 2,3-dioxygenase.

The effect of intraperitoneal administration of phenobarbital (80 mg kg-1 body weight) and tryptophan (200 mg kg-1 body weight), separately or in combination, on the microsomal content of cytochrome P-450 and the activity of tryptophan 2,3-dioxygenase (EC 1.13.11.11) in Wistar rat liver was determined at different time intervals after injection. There was an increase in the amount of cytochrome P-450 within 12 h of administration of a single dose of phenobarbital which was maintained over the next 12 h. Tryptophan had no effect on the amount of cytochrome P-450, but administration of tryptophan in combination with phenobarbital blocked the increase that was found after administration of phenobarbital alone. Both phenobarbital and tryptophan increased tryptophan 2,3-dioxygenase activity (total enzyme and holoenzyme) but had different effects on the rate of activation and the degree of saturation of the enzyme with haem. Administration of tryptophan and phenobarbital in combination invoked the same effect as tryptophan alone. Significant activation of the holoenzyme was found, when tryptophan was administered 2 h after phenobarbital administration. It is proposed that combined administration of phenobarbital and tryptophan leads to substrate stabilisation of tryptophan 2,3-dioxygenase, and that this is accompanied by the binding of the newly synthesised haem, thus making haem unavailable for formation of cytochrome P-450.