Effect of Psychotropic Drugs on the 21-Hydroxylation of Neurosteroids, Progesterone and Allopregnanolone, Catalyzed by Rat CYP2D4 and Human CYP2D6 in the Brain

Abstract

Progesterone (PROG) not only is one of the female steroid hormones secreted from the placenta and corpus luteum but also has various functions in the central nervous system as a neurosteroid in the brain.1,2) PROG has the ability to increase myelin-specific protein levels and to enhance the g-aminobutyric acid (GABA)-induced chloride current, 2,3) and the PROG metabolites, 3a-hydroxy-5a-pregnan-20-one (allopregnanolone, ALLO) and 3a,5a-tetrahydrodeoxycorticosterone, act as positive allosteric modulators of GABA type A receptors, and thereby reduce brain excitability and elicit sedative-hypnotic, anxiolytic, and anticonvulsant effects. 4)These neurosteroids are eliminated via the metabolic pathways, including the hydroxylation at position C21. 5)Cytochrome P450s (CYP) comprise a superfamily of enzymes that catalyze the oxidation of a wide variety of xenobiotic chemicals including drugs, carcinogens, and steroids. [6][7][8] In spite of the fact that CYP2D6 constitutes only 2-9% of constitutively expressed hepatic P450s among humans, 9,10) it plays important roles in the metabolism of a wide range of therapeutic agents, including drugs affecting the central nervous system. 5,8,11,12) Interestingly, CYP2D6 is expressed in the human brain, especially the midbrain, 13) as well as in the liver. In addition, CYP2D4 mRNA is expressed in the rat brain, 14,15) and the reverse transcriptase-polymerase chain reaction (RT-PCR) product from CYP2D4, the predominant CYP2D isoform in the rat brain, is more abundant in the cerebellum, striatum, pons, and medulla oblongata. 16)However, the physiological and pharmacological functions of CYP2D isoforms in the brain are still unknown.We have demonstrated that CYP2D6 catalyzes the 2b, 6b-, 16a-, and 21-hydroxylation of PROG, 17,18) and that PROG 2b-and 21-hydroxylation activities in rat brain microsomes are completely inhibited by CYP2D antibodies, suggesting that CYP2D may be involved in the regulation (metabolism and/or synthesis) of endogenous neuroactive steroids, such as PROG and its derivatives, in the brain.18) Additionally, we have reported that the 21-hydroxylation of ALLO as well as PROG and 17a-PROG is catalyzed by CYP2D isoforms in the brain. 5,15) Many of the psychotropic drugs, including fluoxetine (a selective serotonin reuptake inhibitor, SSRI), imipramine (a tricyclic antidepressant and a serotonin and noradrenaline reuptake inhibitor), and desipramine (a noradrenaline reuptake inhibitor), are metabolized by CYP2D and/or inhibit the CYP2D-mediated metabolic activities. 8,15,[19][20][21][22][23] One of the dopamine uptake sites in the brain displays high affinity for dopamine uptake inhibitors such as mazindol, a noradrenaline reuptake inhibitor. 24,25) The other site displays rather high affinity for piperizine derivatives and has been termed the piperazine acceptor site. 26) GBR12909 (vanoxerine) is a potent inhibitor of both the binding of GBR12935, a piperizine derivative, and CYP2D6 activity. 27) We have demonstrated that the GBR12935 binding is reduced by CYP2D su...

Effect of Cytochrome P450 (CYP) 2D6 Genetic Polymorphism on the Inhibitory Action of Antidepressants on CYP2D6-Mediated Dopamine Formation from p-Tyramine

“…Values are means of duplicate or triplicate determinations. In addition, we previously reported that psychotropic drugs, such as imipramine, desipramine, and fluoxetine, inhibited 21-hydroxylation of progesterone and allopregnanolone (a neuroactive steroid) mediated by CYP2D6 and CYP2D4 (39). In the present study, we found that imipramine and desipramine, which are tricyclic antidepressants (22)(23)(24), competitively or noncompetitively inhibited dopamine formation from p-tyramine.…”

Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6

“…The K i values of CBD were 1.16 to 2.69 M, indicating that the inhibitory effect of CBD on CYP2D6 activity is much stronger than that of progesterone. Compared with typical CYP2D6 inhibitors, the inhibitory effect of CBD on recombinant CYP2D6-mediated activity is comparable to those of (S)-nolfluoxetine (K i ϭ 0.84 M), (S)-fluoxetine (K i ϭ 1.27 M) (Shen et al, 2007), desipramine (K i ϭ 1.0 M), and imipramine (K i ϭ 1.4 M) (Niwa et al, 2008). The inhibitory effect of CBD on HLM-mediated CYP2D6 activity is as potent as those of (S,R)-fluoxetine (K i ϭ 1.6 M), desipramine (K i ϭ 1.7 M) (Ball et al, 1997), and 3,4-methylenedioxyamphetamine (K i ϭ 1.8 M) (Wu et al, 1997).…”

Studies on Neurosteroids XXVI. Fluoxetine-Evoked Changes in Rat Brain and Serum Levels of Neuroactive Androgen, 5.ALPHA.-Androstane-3.ALPHA.,17.BETA.-diol

“…The causes for this could be as follows: 1) Fluox inhibits the cytochrome P450 (CYP) 2D4-mediated 21-hydroxylation of AP, which is one of the main elimination pathways of AP in the brain. 14) Therefore, it is inferred that not only the enhanced AP synthesis, but also the decreased AP metabolic elimination by Fluox dramatically elevated the brain AP level. 2) It has been reported that in the brain, the 17b-hydroxysteroid oxidative activity is higher than the 17-ketosteroid reductive activity for various steroids.…”