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8 Jta IAu WUVc OGvm 2 X Ei O68 BVC T2 Buh P
8 Jta IAu WUVc OGvm 2 X Ei O68 BVC T2 Buh P
8 Jta IAu WUVc OGvm 2 X Ei O68 BVC T2 Buh P
Review
Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland
Abstract:
This article focuses on recent research on the cytochrome P450 2D (CYP2D) catalyzed synthesis of the monoaminergic neurotransmit-
ters dopamine and serotonin in the brain and on the influence of psychotropic drugs on the activity of brain CYP2D. Recent in vitro and
in vivo studies performed in rodents indicate that dopamine and serotonin may be formed in the brain via alternative CYP2D-mediated
pathways, i.e., tyramine hydroxylation and 5-methoxytryptamine O-demethylation, respectively. The contribution of these alternative
pathways to the total synthesis of brain neurotransmitters may be higher in humans and may be significantly increased under specific
conditions, such as tyrosine hydroxylase and amino acid decarboxylase or tryptophan hydroxylase deficiency. These alternative path-
ways of neurotransmitter synthesis may also become more efficient when the CYP2D enzyme is mutated or activated by inducers (e.g.,
alcohol, nicotine, psychotropics), which may be of importance in some neurodegenerative or psychiatric diseases.
In addition to the previously observed influence of antidepressants and neuroleptics on CYP2D in the liver, the investigated drugs
also produce an effect on CYP2D in the brain. However, their effect on brain CYP2D is different than that in the liver and is
structure-dependent. The observed psychotropic drug-brain CYP2D interactions may be important for the metabolism of endoge-
nous neuroactive substrates (e.g., monoaminergic neurotransmitters, neurosteroids) and for the local biotransformation of drugs.
The results are discussed with regard to the contribution of CYP2D to the total synthesis of neurotransmitters in the brain in vivo as
well as the possible significance of these alternative pathways in specific physiological and pathological conditions and in the phar-
macological actions of psychotropic drugs.
Key words:
brain, cytochrome P450, dopamine, serotonin, antidepressants, neuroleptics
In vivo studies
Using CYP2D6-transgenic mice, liver microsomes, spect (one-fifth of that of CYP2D2). Thus, the reac-
and recombinant enzymes, Yu et al. [42] demon- tion of 5-methoxytryptamine O-demethylation to se-
strated that the human CYP2D6 isoform was capable rotonin in rats is less specifically catalyzed by
of catalyzing the O-demethylation of 5-methoxy- CYP2D than is the reaction of tyramine hydroxylation
tryptamine to serotonin. The functional importance of to dopamine [5, 19].
that reaction was shown in peripheral tissues by meas- An experiment with human liver microsomes de-
uring the plasma concentration of serotonin after iv rived from individuals possessing the allelic variant
injection of 5-methoxytryptamine into wild-type and CYP2D6*4*4 indicated that a genetic defect in
CYP2D6-transgenic mice. The reaction of serotonin CYP2D influences serotonin metabolism. The results
regeneration from 5-methoxytryptamine closes the of our study demonstrate that rat CYP2D isoforms are
cycle of melatonin-serotonin biochemical transforma- less efficient at catalyzing 5-methoxytryptamine O-
tions [42], and the chemistry of the O-demethylation demethylation to serotonin than is human CYP2D6
reaction of 5-methoxytryptamine to serotonin by and suggest that this reaction proceeds in the human
CYP2D6 was demonstrated by Schyman et al. [33]. brain at a higher rate than in the rat brain [19]. Thus,
5-Methoxytryptamine is an endogenous trace amine brain CYP2D is likely to positively influence the nor-
that is formed mainly by the deacetylation of mela- mal levels of the indolamines serotonin and mela-
tonin in the pineal gland [2]. However, 5-methoxy- tonin, with both being of antidepressive importance.
tryptamine has also been found in the raphe nuclei in
the brain stem [31], with the latter containing the cell
In vivo studies
bodies of serotonin neurons.
Because 5-methoxytryptamine and CYP2D are in
close proximity in the brain, the O-demethylation of As mentioned above, the CYP2D-catalyzed O-de-
5-methoxytryptamine to serotonin may occur to pre- methylation of 5-methoxytryptamine has been shown
vent the deprivation of the biological activity of indol- in vitro using rat brain microsomes [19]. The follow-
ethylamines by monoamine oxidase (MAO). This up study on rat brain demonstrated the in vivo forma-
may constitute an alternative pathway (to tryptophan tion of serotonin from 5-methoxytryptamine via cyto-
hydroxylation) of serotonin formation in the brain. chrome P450 in a brain microdialysis model [7]. The
microdialysis probe was implanted into the striatum,
and an increase in the extracellular serotonin level
In vitro studies
was observed after 5-methoxytryptamine given intra-
A recent in vitro study of ours provided new evidence structurally. The CYP2D inhibitor quinine decreased
for the hypothesis that the O-demethylation of 5-me- this 5-methoxytryptamine-elevated concentration of
thoxytryptamine to serotonin may occur in the brain serotonin in the striatum, and the effect was more pro-
[19]. Serotonin was found to be synthesized from nounced after the inhibition of the classical pathway
5-methoxytryptamine in different rat brain structures, of serotonin synthesis. The results indicate that the in
with the highest rate being observed in cerebellum- vivo CYP2D-catalyzed synthesis of serotonin from
derived microsomes. The two selective CYP2D in- 5-methoxytryptamine may occur in the rat brain.
hibitors used in our study, quinine and fluoxetine, de- The involvement of CYP2D in melatonin-serotonin
creased the rate of this reaction, with quinine being transformation in the brain was investigated in an-
an approximately fourfold more potent inhibitor of other in vivo study in rats [20]. Melatonin (ip) raised
5-methoxytryptamine O-demethylation to serotonin the concentration of serotonin in different brain struc-
than of tyramine hydroxylation to dopamine [5, 19]. tures, whereas quinine, a CYP2D inhibitor, adminis-
Essentially, the isoforms of the CYP2D subfamily, tered prior to melatonin prevented this elevation in se-
CYP2D1/2 and CYP2D4/18 (the major brain CYP2D rotonin concentration. The obtained results provide
isoforms), are capable of catalyzing the O-demethyl- further in vivo evidence that the CYP2D-mediated
ation of 5-methoxytryptamine to serotonin (Fig. 2B). synthesis of serotonin occurs in the rat brain.
Of the other rat CYP isoforms studied (1A1/2, 2A1/2, Recently, Cheng et al. [9] observed that the level of
2B1, 2C6/11/13, 2E1, and 3A1/2), isoform CYP2C13 serotonin and its metabolite 5-HIAA in the brain of
showed an activity of approximately one-third of that CYP2D6-transgenic mice was higher than in wild-
of CYP2D2, whereas the other CYP isoforms (2B, type mice and that the CYP2D6-transgenic mice were
2C6, 2E1, and 3A) displayed low activity in this re- less susceptible to anxiety. Thus, parallel studies per-
5-methoxytryptamine via the alternative CYP2D- 255–485 µM) than when added to liver microsomes
mediated pathway in rodents. It may be assumed that (K = 1–45 µM). This finding may be due to the
i
the same pathway also functions in the human brain. stronger affinity of these drugs for liver CYP2D2 (K i
Brain serotonin has been implicated in the patho- = 2.7 and 1.25 µM for imipramine and fluoxetine, re-
physiology of different psychiatric disorders (such as spectively) than for brain CYP2D4 (K = 25 and
i
depression, anxiety, schizophrenia) and in the mecha- 10 µM for imipramine and fluoxetine, respectively)
nism of action of psychotropic drugs (e.g., antidepres- [18]. Imipramine, fluoxetine, and thioridazine inhib-
sants, anxiolytics, antipsychotics). The in vivo studies ited the activity of the cDNA-expressed CYP2D2
indicate that this alternative pathway of serotonin syn- isoenzyme (hepatic) several times more potently than
thesis may contribute to the overall serotonin content the activity of CYP2D4 (cerebral). However, perazine
in different regions of the brain, and this situation may diminished the activities of both isoforms to a similar
particularly occur when the classical pathway via extent, whereas nefazodone only inhibited the activity
tryptophan hydroxylase is deficient and/or when of CYP2D4, without affecting that of CYP2D2. The
CYP2D is activated by inducers. Therefore, the alter- observed differences in the inhibitory effect of psy-
native pathway of serotonin synthesis may be consid- chotropics in the brain and liver may also be due to
ered as a target for the pharmacological action of different levels of non-specific binding and the rela-
drugs in the course of treatment of psychiatric dis- tively low CYP level in the brain and, subsequently,
eases. higher protein concentration used for experiments
with brain microsomes [18]. However, the low K val-
i
Tab. 1. The effect of chronic treatment with psychotropic drugs on the activity and protein levels of CYP2D in different brain structures (a com-
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tivity or protein level. According to Haduch et al. [18] and Hedlund et al. [22]a
IMI ¯ – – – – – – – –
FLU ¯ ¯ß – ¯ß – Ý – – –
MRT – – – – – – – –
NEF ¯ – – – – – – – –
TIOR ¯ ¯ß – Ý ¯Ý Ý – – –
CLOZ –a ¯ß – – ß Ý Ýa Ý Ý
IMI – imipramine, FLU – fluoxetine, MRT – mirtazapine, NEF – nefazodone, TIOR – thioridazine, CLOZ – clozapine
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