The effect of psychotropic drugs on cytochrome P450 2D (CYP2D) in rat brain

The aim of the study was to investigate the influence of selected antidepressants and neuroleptics on the protein level and activity of cytochrome P450 2D (CYP2D) in rat brain. The obtained results showed that imipramine, fluoxetine, nefazodone, thioridazine and perazine, added to brain microsomes of control rats, inhibited CYP2D activity to a lower extent (Ki = 255-485 μM) than when added to liver microsomes (Ki = 1-45 μM), which may result from their stronger affinity for liver CYP2D2 (Ki = 2.7 and 1.25 μM for imipramine and fluoxetine, respectively) than for brain CYP2D4 (Ki = 25 and 10 μM for imipramine and fluoxetine, respectively), as well as from their high non-specific binding in brain microsomes. Two-week treatment with fluoxetine evoked decreases in the level and activity of CYP2D in the striatum and the nucleus accumbens. In contrast, fluoxetine increased CYP2D expression in the cerebellum, while nefazodone considerably enhanced the activity (but not the protein level) of CYP2D in the truncus cerebri. Imipramine and mirtazapine (active in the liver) did not affect brain CYP2D. Chronic thioridazine decreased CYP2D activity in the substantia nigra and nucleus accumbens, but significantly increased that activity in the striatum and cerebellum. Clozapine significantly enhanced CYP2D activity in the truncus cerebri. In conclusion, psychotropics influence CYP2D in the brain, but their effect is different than in the liver and depends on the cerebral structure. The observed psychotropics-brain CYP2D interactions may be important for the metabolism of neurosteroids and monoaminergic neurotransmitters, and for the local biotransformation of drugs.