CYP2C19 polymorphism affects personality traits of Japanese females

Ishii, Genki; Suzuki, Akihito; Oshino, Shingo; Shiraishi, Hiroaki; Otani, Koichi

doi:10.1016/j.neulet.2006.10.012

Cited by 39 publications

(28 citation statements)

References 27 publications

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“…It is conceivable that alterations in levels of brain CYP enzymes and activity could cause subtle shifts in these endogenous neurochemical pathways, which could impact on neuropsychiatric conditions such as mood and overall mental health. Indeed, this may be a contributing factor to the clinical observations of personality differences between CYP2D6 extensive and poor metabolizers (Bertilsson et al, 1989;Llerena et al, 1993;Kirchheiner et al, 2006;Dorado et al, 2007), and between CYP2C19 extensive and poor metabolizers (Ishii et al, 2007;Yasui-Furukori et al, 2007).…”

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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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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“…70 Similar associations of genotype and personality or mood have been observed for CYP2C19, CYP2E1 and CYP19 (aromatase). [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%

Cytochrome P450–mediated drug metabolism in the brain

Miksys

Tyndale

2013

J Psychiatry Neurosci

116

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“…Since the dealkylating activity of CYP1A1 is well-known for ethoxylated substrates [114,115,156], NAS formation from melatonin seems likely for this isoenzyme, too. In addition to other CYPs not related to melatonin metabolism, CYP1A2 [60,88,126], CYP1A1 [60,88], CYP1B1 [79,88], and CYP2C19 [58,59,159] are also expressed in the brain. The presence of these CYP isoenzymes indicates that, at least, a certain fraction of melatonin should be either 6-hydroxylated or O-demethylated in the CNS (Fig.…”

Section: Cytochrome P 450 Metabolismmentioning

confidence: 99%

Melatonin Metabolism in the Central Nervous System

Hardeland¹

2010

114

110

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Abstract:The metabolism of melatonin in the central nervous system is of interest for several reasons. Melatonin enters the brain either via the pineal recess or by uptake from the blood. It has been assumed to be also formed in some brain areas. Neuroprotection by melatonin has been demonstrated in numerous model systems, and various attempts have been undertaken to counteract neurodegeneration by melatonin treatment. Several concurrent pathways lead to different products. Cytochrome P 450 subforms have been demonstrated in the brain. They either demethylate melatonin to Nacetylserotonin, or produce 6-hydroxymelatonin, which is mostly sulfated already in the CNS. Melatonin is deacetylated, at least in pineal gland and retina, to 5-methoxytryptamine. N 1 -acetyl-N 2 -formyl-5-methoxykynuramine is formed by pyrrole-ring cleavage, by myeloperoxidase, indoleamine 2,3-dioxygenase and various non-enzymatic oxidants. Its product, N 1 -acetyl-5-methoxykynuramine, is of interest as a scavenger of reactive oxygen and nitrogen species, mitochondrial modulator, downregulator of cyclooxygenase-2, inhibitor of cyclooxygenase, neuronal and inducible NO synthases. Contrary to other nitrosated aromates, the nitrosated kynuramine metabolite, 3-acetamidomethyl-6-methoxycinnolinone, does not re-donate NO. Various other products are formed from melatonin and its metabolites by interaction with reactive oxygen and nitrogen species. The relative contribution of the various pathways to melatonin catabolism seems to be influenced by microglia activation, oxidative stress and brain levels of melatonin, which may be strongly changed in experiments on neuroprotection. Many of the melatonin metabolites, which may appear in elevated concentrations after melatonin administration, possess biological or pharmacological properties, including N-acetylserotonin, 5-methoxytryptamine and some of its derivatives, and especially the 5-methoxylated kynuramines.

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CYP2C19 polymorphism affects personality traits of Japanese females

Cited by 39 publications

References 27 publications

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

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

Cytochrome P450–mediated drug metabolism in the brain

Melatonin Metabolism in the Central Nervous System

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