Dopamine Formation from Tyramine by CYP2D6

Hiroi, Toyoko; Imaoka, Shingi; Funae, Yoshihiko

doi:10.1006/bbrc.1998.9232

Cited by 208 publications

(129 citation statements)

References 27 publications

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“…1,10 Later CYP2D6 was reported to be involved in the biotransformation of several neurotransmitters functionally impaired in psychiatric disorders including schizophrenia, such as dopamine, serotonin and neuroactive steroids. [21][22][23] In view of the present findings, our hypothesis is that CYP2D6 is associated not only with interindividual variability in the response to antipsychotic drugs, but also with the vulnerability to psychiatric disorders such as schizophrenia.…”

Section: Discussionmentioning

confidence: 95%

Low frequency of CYP2D6 poor metabolizers among schizophrenia patients

et al. 2007

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CYP2D6 has been suggested to be functionally similar to the dopamine transporter. The present study was aimed at analysing the frequency of CYP2D6 alleles and genotype among schizophrenic patients compared to healthy volunteers. CYP2D6 *3, *4, *5, *6, *10 and duplicated alleles were analysed in 128 unselected schizophrenia inpatients (SP) and 142 unrelated white European Spanish healthy volunteers (HV). SP and HV with 42, 2, 1 or 0 CYP2D6 active genes were 4.7, 64.8, 28.1 and 2.3%, and 6.3, 52.1, 33.1 and 8.5%, respectively. The frequency of homozygous for CYP2D6 inactive alleles or poor metabolizers (PMs) was lower (Po0.05) in SP than in HV. Furthermore, the frequency of CYP2D6 inactive alleles was also lower in SP than in HV (16.8 vs 25.7; Po0.05), specifically the CYP2D6*6 allele was not found among patients. The present study shows a lower frequency of PMs in schizophrenic patients than in healthy volunteers supporting the hypothesis of a potential role of CYP2D6 in the vulnerability to schizophrenia.

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Section: Discussionmentioning

confidence: 95%

Low frequency of CYP2D6 poor metabolizers among schizophrenia patients

et al. 2007

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“…CYP2E1 contributes to the metabolism of arachidonic acid, fatty acids, and estrogenic metabolites (Lieber, 1999;Ohe et al, 2000). CYP2D6 metabolizes progesterone (Hiroi et al, 2001;Niwa et al, 2004) and biotransforms tyramine to dopamine (Hiroi et al, 1998;Niwa et al, 2004). CYP2D6 mediates several pathways in the cyclical metabolic interconvertions of endogenous indolethylamines, for example the regeneration of serotonin from 5-methoxytryptamine (Yu et al, 2003a, b).…”

Section: Discussionmentioning

confidence: 99%

Brain Drug-Metabolizing Cytochrome P450 Enzymes are Active In Vivo, Demonstrated by Mechanism-Based Enzyme Inhibition

Miksys

Tyndale

2008

Neuropsychopharmacol

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Individuals vary in their response to centrally acting drugs, and this is not always predicted by drug plasma levels. Central metabolism by brain cytochromes P450 (CYPs) may contribute to interindividual variation in response to drugs. Brain CYPs have unique regional and cell-type expression and induction patterns, and they are regulated independently of their hepatic isoforms. In vitro, these enzymes can metabolize endogenous and xenobiotic substrates including centrally acting drugs, but there is no evidence to date of their in vivo function. This has been difficult to demonstrate in the presence of hepatically derived metabolites that may cross the blood-brain barrier. In addition, because of the membrane location of brain CYPs and the rate limiting effect of endogenous heme levels on the activity and appropriate membrane insertion of some induced CYPs, it has been unclear whether sufficient cofactors and coenzymes are present for constitutive and induced CYP forms to be enzymatically active. We have developed a method using a radiolabeled mechanism-based inhibitor of CYP2B1, 3 H-8-methoxypsoralen, to demonstrate for the first time that both the constitutive and induced forms of this enzyme are active in situ in the living rat brain. This methodology provides a novel approach to assess the function of enzymes in extrahepatic tissues, where expression levels are often low. Selective induction of metabolically active drug metabolizing enzymes in the brain may also provide ways to control prodrug activation in specific brain regions as a novel therapeutic avenue.

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“…[71][72][73][74] These enzymes are expressed in the brain, and they can all metabolize endogenous neural substrates, suggesting that these genotype-phenotypepersonality associations may be manifested, at least in part, through altered brain metabolism of CNS neurochemicals. CYP2D6 can participate in the metabolism of neurochemicals that influence psychological state, such as the formation of the catecholamines dopamine from tyramine 62,63,75 and serotonin from 5-methoxytryptamine 76,77 and the metabolism of the endogenous cannabinoid anandamide 78 and the neurosteroid progesterone.…”

Section: Endogenous Brain Cyp Functionmentioning

confidence: 99%