Effect of Phenobarbital and3,4-Benzpyrene Treatment of Rats on the Microsomal Binding and Hydroxylation of Nortriptyline and Desmethyl-imipramine: Evidence for Qualitative Changes in Cytochrome P-450-Ligand Interaction following Phenobarbital Pretreatment

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Abstract
1. Tricyclic antidepressant drugs bind to cytochrome P-450 with very high affinities and are useful tools for studying ligand interaction with cytochrome P-450 in different microsomal preparations. The effects of three days treatment of rats with phenobarbital and 3,4-benzpyrene on the microsomal binding and hydroxylation of two such drugs nortriptyline (NT) and desmethylimipramine (DMI) are described. 2. Treatment with 3,4-benzpyrene slightly increased the rate of hydroxylation of NT and DMI, whereas repeated administration of phenobarbital reduced the same rates. 3. In microsomes from untreated and 3,4-benzpyrene-treated animals these drugs elicited a type I spectral change, but in microsomes from phenobarbitaltreated animals a type II spectral change was obtained. It was not possible to obtain a type II spectral change with NT or DMI in control microsomes upon addition of phenobarbital in vitro 4. Thus, it seems that phenobarbital treatment, by affecting cytochrome P-450 or its microenvironment, causes a qualitative change in the ligand interaction between the cytochrome and NT and DMI. This may explain the slightly decreased rates of hydroxylation of these drugs observed with microsomes from phenobarbital-treated rats.