Abstract
Polymorphic cytochrome P450 2D6 (CYP2D6) is expressed in several types of central neurons but its function in human brain is currently unknown. Using recombinant enzymes and CYP2D6-transgenic mice, we established that 5-methoxytryptamine (5-MT), a metabolite and precursor of melatonin, is a specific and high-turnover endogenous substrate of CYP2D6. This potent serotonergic neuromodulator in numerous physiological systems binds tightly to recombinant CYP2D6 enzyme with an equilibrium dissociation constant (Ks) of 23.4 μmol/l, and is O-demethylated to serotonin (5-hydroxytryptamine, 5-HT) with a high turnover of 51.7 min-1 and low Michaelis-Menten constant of 19.5 μmol/l. The production of 5-HT from 5-MT catalyzed by CYP2D6 was inhibited by selective serotonin reuptake inhibitors, and their inhibition potency (Ki, μmol/l) decreased in the order of fluoxetine (0.411 ) > norfluoxetine (1.38) > fluvoxamine (10.1) > citalopram (10.9). Liver microsomes prepared from CYP2D6-transgenic mice showed about 16-fold higher 5-MT O-demethylase activity than that from wild-type mice. After the intravenous co-administration of 5-MT (10 mg/kg) and pargyline (20 mg/kg), serum 5-HT level was about 3-fold higher in CYP2D6-transgenic mice than wild-type mice. When dosed with α,α,β,β-d4-5-MT, α,α,β,β-d4-5-HT was detected in CYP2D6 transgenic mouse serum, and its content was much higher than wild-type mouse, α,α,β,β-d4-5-HT was not produced in CYP2D6-transgenic mice pretreated with quinidine. The regeneration of 5-HT from 5-MT provides the missing link in the serotonin-melatonin cycle. Up to 10% of the population lacks this enzyme. It is proposed that this common inborn error in 5-MT O-demethylation to serotonin influences a range of neurophysiologic and pathophysiologic events.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 173-181 |
| Number of pages | 9 |
| Journal | Pharmacogenetics |
| Volume | 13 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2003 |
| Externally published | Yes |
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Keywords
- 5-Hydroxytryptamine
- 5-Methoxytryptamine
- CYP2D6
- Melatonin
ASJC Scopus subject areas
- Genetics
- Pharmacology, Toxicology and Pharmaceutics(all)
Cite this
Regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6. / Yu, Aiming; Idle, Jeffrey R.; Byrd, Linda G.; Krausz, Kristopher W.; Küpfer, Adrian; Gonzalez, Frank J.
In: Pharmacogenetics, Vol. 13, No. 3, 03.2003, p. 173-181.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Regeneration of serotonin from 5-methoxytryptamine by polymorphic human CYP2D6
AU - Yu, Aiming
AU - Idle, Jeffrey R.
AU - Byrd, Linda G.
AU - Krausz, Kristopher W.
AU - Küpfer, Adrian
AU - Gonzalez, Frank J.
PY - 2003/3
Y1 - 2003/3
N2 - Polymorphic cytochrome P450 2D6 (CYP2D6) is expressed in several types of central neurons but its function in human brain is currently unknown. Using recombinant enzymes and CYP2D6-transgenic mice, we established that 5-methoxytryptamine (5-MT), a metabolite and precursor of melatonin, is a specific and high-turnover endogenous substrate of CYP2D6. This potent serotonergic neuromodulator in numerous physiological systems binds tightly to recombinant CYP2D6 enzyme with an equilibrium dissociation constant (Ks) of 23.4 μmol/l, and is O-demethylated to serotonin (5-hydroxytryptamine, 5-HT) with a high turnover of 51.7 min-1 and low Michaelis-Menten constant of 19.5 μmol/l. The production of 5-HT from 5-MT catalyzed by CYP2D6 was inhibited by selective serotonin reuptake inhibitors, and their inhibition potency (Ki, μmol/l) decreased in the order of fluoxetine (0.411 ) > norfluoxetine (1.38) > fluvoxamine (10.1) > citalopram (10.9). Liver microsomes prepared from CYP2D6-transgenic mice showed about 16-fold higher 5-MT O-demethylase activity than that from wild-type mice. After the intravenous co-administration of 5-MT (10 mg/kg) and pargyline (20 mg/kg), serum 5-HT level was about 3-fold higher in CYP2D6-transgenic mice than wild-type mice. When dosed with α,α,β,β-d4-5-MT, α,α,β,β-d4-5-HT was detected in CYP2D6 transgenic mouse serum, and its content was much higher than wild-type mouse, α,α,β,β-d4-5-HT was not produced in CYP2D6-transgenic mice pretreated with quinidine. The regeneration of 5-HT from 5-MT provides the missing link in the serotonin-melatonin cycle. Up to 10% of the population lacks this enzyme. It is proposed that this common inborn error in 5-MT O-demethylation to serotonin influences a range of neurophysiologic and pathophysiologic events.
AB - Polymorphic cytochrome P450 2D6 (CYP2D6) is expressed in several types of central neurons but its function in human brain is currently unknown. Using recombinant enzymes and CYP2D6-transgenic mice, we established that 5-methoxytryptamine (5-MT), a metabolite and precursor of melatonin, is a specific and high-turnover endogenous substrate of CYP2D6. This potent serotonergic neuromodulator in numerous physiological systems binds tightly to recombinant CYP2D6 enzyme with an equilibrium dissociation constant (Ks) of 23.4 μmol/l, and is O-demethylated to serotonin (5-hydroxytryptamine, 5-HT) with a high turnover of 51.7 min-1 and low Michaelis-Menten constant of 19.5 μmol/l. The production of 5-HT from 5-MT catalyzed by CYP2D6 was inhibited by selective serotonin reuptake inhibitors, and their inhibition potency (Ki, μmol/l) decreased in the order of fluoxetine (0.411 ) > norfluoxetine (1.38) > fluvoxamine (10.1) > citalopram (10.9). Liver microsomes prepared from CYP2D6-transgenic mice showed about 16-fold higher 5-MT O-demethylase activity than that from wild-type mice. After the intravenous co-administration of 5-MT (10 mg/kg) and pargyline (20 mg/kg), serum 5-HT level was about 3-fold higher in CYP2D6-transgenic mice than wild-type mice. When dosed with α,α,β,β-d4-5-MT, α,α,β,β-d4-5-HT was detected in CYP2D6 transgenic mouse serum, and its content was much higher than wild-type mouse, α,α,β,β-d4-5-HT was not produced in CYP2D6-transgenic mice pretreated with quinidine. The regeneration of 5-HT from 5-MT provides the missing link in the serotonin-melatonin cycle. Up to 10% of the population lacks this enzyme. It is proposed that this common inborn error in 5-MT O-demethylation to serotonin influences a range of neurophysiologic and pathophysiologic events.
KW - 5-Hydroxytryptamine
KW - 5-Methoxytryptamine
KW - CYP2D6
KW - Melatonin
UR - http://www.scopus.com/inward/record.url?scp=0037342251&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037342251&partnerID=8YFLogxK
U2 - 10.1097/00008571-200303000-00007
DO - 10.1097/00008571-200303000-00007
M3 - Article
C2 - 12618595
AN - SCOPUS:0037342251
VL - 13
SP - 173
EP - 181
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
SN - 1744-6872
IS - 3
ER -