Faculty Profiles - ASANUMA Masato

Papers - ASANUMA Masato

Division display 81 - 100 of about 318 ／ All the affair displays >>

A study on bioactivity and function of chemical compounds in food and foodstuff: search for angiotensin 1-converting enzyme inhibitory substances in some edible mushrooms using fluorescent substrate

Bulletin of Kyushu Nutrition Welfare University 6 ( 6 ) 9 - 20 2009.12

A study on bioactivity and function of chemical compounds in food and foodstuff: effect of phytic acid on cultured dopamine neuronal cells

Bulletin of Kyushu Nutrition Welfare University 6 ( 6 ) 75 - 86 2009.12

Lithium treatment elongates primary cilia in the mouse brain and in cultured cells Reviewed

Ko Miyoshi, Kyosuke Kasahara, Ikuko Miyazaki, Masato Asanuma

Biochemical and Biophysical Research Communications 388 ( 4 ) 757 - 762 2009.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

The molecular mechanisms underlying the therapeutic effects of lithium, a first-line antimanic mood stabilizer, have not yet been fully elucidated. Treatment of the algae Chlamydomonas reinhardtii with lithium has been shown to induce elongation of their flagella, which are analogous structures to vertebrate cilia. In the mouse brain, adenylyl cyclase 3 (AC3) and certain neuropeptide receptors colocalize to the primary cilium of neuronal cells, suggesting a chemosensory function for the primary cilium in the nervous system. Here we show that lithium treatment elongates primary cilia in the mouse brain and in cultured cells. Brain sections from mice chronically fed with Li(2)CO(3) were subjected to immunofluorescence study. Primary cilia carrying both AC3 and the receptor for melanin-concentrating hormone (MCH) were elongated in the dorsal striatum and nucleus accumbens of lithium-fed mice, as compared to those of control animals. Moreover, lithium-treated NIH3T3 cells and cultured striatal neurons exhibited elongation of the primary cilia. The present results provide initial evidence that a psychotropic agent can affect ciliary length in the central nervous system, and furthermore suggest that lithium exerts its therapeutic effects via the upregulation of cilia-mediated MCH sensing. These findings thus contribute novel insights into the pathophysiology of bipolar mood disorder and other psychiatric diseases. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2009.08.099

Web of Science

researchmap

Effects of galantamine on L-NAME-induced behavioral impairment in Y-maze task in mice Reviewed

Ken-ichi Tanaka, Takao Yagi, Ryosuke Shimakoshi, Koji Azuma, Takeshi Nanba, Hiroya Ogo, Akiko Tamura, Masato Asanuma

Neuroscience Letters 462 ( 3 ) 235 - 238 2009.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Nitric oxide (NO) may play a role in the established processes of learning and memory. We examined the effects of N-omega-nitro-L-arginine methylester (L-NAME), a nonselective inhibitor of NO synthase (NOS), on the performance of mice in a Y-maze task. L-NAME (100 mg/kg) markedly impaired spontaneous alternation behavior. However, galantamine (0.5 mg/kg) significantly attenuated this L-NAME-induced impairment. To clarify the molecular basis underlying galantamine's protective effects against L-NAME-induced impairment of spontaneous alternation behavior, we tested the ability of mecamylamine, an antagonist of nicotinic ACh receptor (nAChR), and scopolamine, an antagonist of muscarinic ACh receptor, to reduce galantamine's protective effects, and found that only the former had such an ability. Galantamine significantly also reduced L-NAME-induced decreases in NOx levels. However, mecamylamine cancelled galantamine's efficacy in countering the L-NAME-induced decrease in NOx levels. In the present study, we have determined that galantamine's protection against L-NAME-induced impairment of spontaneous alternation behavior in the Y-maze task might be mediated mainly by NOergic activation via the nAChR-related pathway. (c) 2009 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2009.07.024

Web of Science

researchmap

Pericentrin, a centrosomal protein related to microcephalic primordial dwarfism, is required for olfactory cilia assembly in mice Reviewed

Ko Miyoshi, Kyosuke Kasahara, Ikuko Miyazaki, Shoko Shimizu, Manabu Taniguchi, Shinsuke Matsuzaki, Masaya Tohyama, Masato Asanuma

FASEB Journal 23 ( 10 ) 3289 - 3297 2009.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：FEDERATION AMER SOC EXP BIOL

The Drosophila pericentrin-like protein has been shown to be essential for the formation of the sensory cilia of chemosensory and mechanosensory neurons by mutant analysis in flies, while the in vivo function of pericentrin, a well-studied mammalian centrosomal protein related to microcephalic primordial dwarfism, has been unclear. To determine whether pericentrin is required for ciliogenesis in mammals, we generated and analyzed mice with a hypomorphic mutation of Pcnt encoding the mouse pericentrin. Immunofluorescence analysis demonstrated that olfactory cilia of chemosensory neurons in the nasal olfactory epithelium were malformed in the homozygous mutant mice. On the other hand, the assembly of motile and primary cilia of non-neuronal epithelial cells and the formation of sperm flagella were not affected in the Pcnt-mutant mice. The defective assembly of olfactory cilia in the mutant was apparent from birth. The mutant animals displayed reduced olfactory performance in agreement with the compromised assembly of olfactory cilia. Our findings suggest that pericentrin is essential for the assembly of chemosensory cilia of olfactory receptor neurons, but it is not globally required for cilia formation in mammals.-Miyoshi, K., Kasahara, K., Miyazaki, I., Shimizu, S., Taniguchi, M., Matsuzaki, S., Tohyama, M., Asanuma, M. Pericentrin, a centrosomal protein related to microcephalic primordial dwarfism, is required for olfactory cilia assembly in mice. FASEB J. 23, 3289-3297 ( 2009). www.fasebj.org

DOI： 10.1096/fj.08-124420

Web of Science

researchmap

Effects of pramipexole on the duration of immobility during the forced swim test in normal and ACTH-treated rats Reviewed

Kouhei Kitagawa, Yoshihisa Kitamura, Toshiaki Miyazaki, Junya Miyaoka, Hiromu Kawasaki, Masato Asanuma, Toshiaki Sendo, Yutaka Gomita

Naunyn-Schmiedebergs Archives of Pharmacology 380 ( 1 ) 59 - 66 2009.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

The dopamine D2/D3 receptor agonist pramipexole has clinically been proven to improve depression or treatment-resistant depression. However, the involvement of the dopamine receptor system on the effect of pramipexole on depression remains unclear. We examined the influence of pramipexole on the duration of immobility during the forced swim test in normal and adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of dopamine receptors in this effect. Additionally, the mechanism by which pramipexole acts in this model was explored specifically in relation to the site of action through the use of microinjections into the intramedial prefrontal cortex and nucleus accumbens. Pramipexole (0.3-1 mg/kg) significantly decreased the duration of immobility in normal and ACTH-treated rats. This effect was blocked by L-741,626, a D2 receptor antagonist, and nafadotride, a D3 receptor antagonist, in normal rats. Furthermore, infusions of pramipexole into the intranucleus accumbens, but not the medial prefrontal cortex, decreased the immobility of normal and ACTH-treated rats during the forced swim test. Taken together, the results of these experiments suggested that pramipexole, administered into the intranucleus accumbens rather than the medial prefrontal cortex, exerted an antidepressant-like effect on ACTH-treated rats via the dopaminergic system. The immobility-decreasing effect of pramipexole may be mediated by dopamine D2 and D3 receptors.

DOI： 10.1007/s00210-009-0405-0

Web of Science

researchmap

Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity Reviewed

Ikuko Miyazaki, Masato Asanuma

Neurochemical Research 34 ( 4 ) 698 - 706 2009.4

Authorship：Last author Language：English Publisher：SPRINGER/PLENUM PUBLISHERS

Dopamine (DA) and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells, primarily due to the generation of highly reactive DA and DOPA quinones. Quinone formation is closely linked to other representative hypotheses such as mitochondrial dysfunction, inflammation, oxidative stress, and dysfunction of the ubiquitin-proteasome system, in the pathogenesis of neurodegenerative diseases such as Parkinson's disease and methamphetamine-induced neurotoxicity. Therefore, pathogenic effects of the DA quinone have focused on dopaminergic neuron-specific oxidative stress. Recently, various studies have demonstrated that some intrinsic molecules and several drugs exert protective effects against DA quinone-induced damage of dopaminergic neurons. In this article, we review recent studies on some neuroprotective approaches against DA quinone-induced dysfunction and/or degeneration of dopaminergic neurons.

DOI： 10.1007/s11064-008-9843-1

Web of Science

researchmap

Reduction of Nuclear Peroxisome Proliferator-Activated Receptor gamma Expression in Methamphetamine-Induced Neurotoxicity and Neuroprotective Effects of Ibuprofen Reviewed

Takeshi Tsuji, Masato Asanuma, Ikuko Miyazaki, Ko Miyoshi, Norio Ogawa

Neurochemical Research 34 ( 4 ) 764 - 774 2009.4

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER/PLENUM PUBLISHERS

We examined changes in nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) in the striatum in methamphetamine (METH)-induced dopaminergic neurotoxicity, and also examined effects of treatment with drugs possessing PPAR gamma agonistic properties. The marked reduction of nuclear PPAR gamma-expressed cells was seen in the striatum 3 days after METH injections (4 mg/kg x 4, i.p. with 2-h interval). The reduction of dopamine transporter (DAT)-positive signals and PPAR gamma expression, and accumulation of activated microglial cells were significantly and dose-dependently attenuated by four injections of a nonsteroidal anti-inflammatory drug and a PPAR gamma ligand, ibuprofen (10 or 20 mg/kg x 4, s.c.) given 30 min prior to each METH injection, but not by either a low or high dose of aspirin. Either treatment of ibuprofen or aspirin, that showed no effects on METH-induced hyperthermia, significantly blocked the METH-induced striatal cyclooxygenase (COX) expression. Furthermore, the treatment of an intrinsic PPAR gamma ligand 15d-PG J2 also attenuated METH injections-induced reduction of striatal DAT. Therefore, the present study suggests the involvement of reduction of PPAR gamma expression in METH-induced neurotoxicity. Taken together with the previous report showing protective effects of other PPAR gamma ligand, these results imply that the protective effects of ibuprofen against METH-induced neurotoxicity may be based, in part, on its anti-inflammatory PPAR gamma agonistic properties, but not on its COX-inhibiting property or hypothermic effect.

DOI： 10.1007/s11064-008-9863-x

Web of Science

researchmap

Dopamine-Induced Behavioral Changes and Oxidative Stress in Methamphetamine-Induced Neurotoxicity Reviewed

Taizo Kita, Ikuko Miyazaki, Masato Asanuma, Mika Takeshima, George C. Wagner

International Review of Neurobiology 88 43 - 64 2009

Effects of L-theanine on cultured dopaminergic neuronal and glial cells

Bulletin of Kyushu Nutrition Welfare University 5 ( 5 ) 69 - 81 2008.12

Dopamine Induces Supernumerary Centrosomes and Subsequent Cell Death through Cdk2 up-Regulation in Dopaminergic Neuronal Cells Reviewed

Francisco J. Diaz-Corrales, Masato Asanuma, Ikuko Miyazaki, Ko Miyoshi, Nobutaka Hattori, Norio Ogawa

Neurotoxicity Research 14 ( 4 ) 295 - 305 2008.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Aggregation of proteins in the centrosome is implicated in the pathophysiology of Parkinson's disease. However, the relevance of the centrosome in neurodegeneration is still obscure. Centrosome duplication is initiated by the cyclin E/cyclin-dependent kinase 2 (Cdk2) complex. The present study determined changes in cyclin E or Cdk2 expression and in the centrosomal structure in dopaminergic neuronal CATH.a cells exposed to 50, 100 and 150 mu M dopamine (DA) for 24 h. DA induced significant increase in Cdk2 protein and cyclin E protein, but not cyclin a mRNA. In DA-treated cells, the intense cyclin E- and Cdk2-immunofluorescence signals were co-localized around large and supernumerary centrosomes, and these two parameters of centrosome amplification were significantly increased compared with the control. Simultaneous co-treatment with DA and a Cdk2 inhibitor blocked centrosome amplification and enhanced cell viability. Our results demonstrated that DA could lead to cyclin E accumulation and Cdk2 up-regulation triggering supernumerary centrosomes and apoptotic cell death.

DOI： 10.1007/BF03033854

Web of Science

researchmap

A study on the effect of chemicals migrated from food and its ingredient in cultured monoamine neuronal cells: effect of docosahexaenoic acid on dopamine-induced neurotoxicity

Bulletin of Kyushu Nutrition Welfare University 5 ( 5 ) 55 - 67 2008.12

Protective effects of interferon-gamma against methamphetamine-induced neurotoxicity (vol 177, pg 123, 2008) Reviewed

Hiroaki Hozumi, Masato Asanuma, Ikuko Miyazaki, Saki Fukuoka, Yuri Kikkawa, Naotaka Kimoto, Yoshihisa Kitamura, Toshiaki Sendo, Taizo Kita, Yutaka Gomita

Toxicology Letters 180 ( 3 ) 231 - 231 2008.8

Effects of HMGB1 on ischemia-reperfusion injury in the rat heart Reviewed

Susumu Oozawa, Shuji Mori, Toru Kanke, Hideo Takahashi, Keyue Liu, Yasuko Tomono, Masato Asanuma, Ikuko Miyazaki, Masahiro Nishibori, Shunji Sano

Circulation Journal 72 ( 7 ) 1178 - 1184 2008.7

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE CIRCULATION SOC

Background Coronary ischemia-reperfusion (I/R) injury causes cardiomyocyte necrosis in a multi-step process that includes an inflammatory reaction. A recent study has suggested that high-mobility group box 1 (HMGB 1) is a late mediator of lethal sepsis and an early mediator of inflammation and necrosis following I/R injury. In the present study a neutralizing monoclonal antibody (mAb) for HMGB1 was used to clarify the role of HMGB 1 in cardiac I/R injury.
Methods and Results Rats underwent 30 min of left coronary artery occlusion followed by 60 min reperfusion. An intravenous injection of anti-HMGB1 mAb or control IgG was administered just before reperfusion. The infarct size was enlarged in the anti-HMGB1 mAb group in comparison with the control group (p<0.05). The treatment of anti-HMGB1 mAb significantly increased the plasma troponin-T and norepinephrine (NE) content in the heart in comparison with the control (p<0.05). Moreover, the production of dihydroxyphenylglycol was reduced in the anti-HMGB1-treated group (p<0.05).
Conclusion This study shows for the first time the effects of treatment with neutralizing anti-HMGB1 mAb on I/R injury in the rat heart. The findings support the novel view that I/R-induced HMGB1 may be an important factor in the modulation of interstitial NE.

DOI： 10.1253/circj.72.1178

Web of Science

researchmap

Dopaminergic neuron-specific oxidative stress caused by dopamine itself Reviewed

Ikuko Miyazaki, Masato Asanuma

Acta Medica Okayama 62 ( 3 ) 141 - 150 2008.6

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Oxidative stress, including the reactive oxygen or nitrogen species generated in the enzymatical oxidation or auto-oxidation of an excess amount of dopamine, is thought to play an important role in dopaminergic neurotoxicity. Dopamine and its metabolites containing 2 hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells, primarily due to the generation of highly reactive dopamine and DOPA quinones. Dopamine and DOPA quinones may irreversibly alter protein function through the formation of 5-cysteinyl-catechols on the proteins. Furthermore, the quinone formation is closely linked to other representative hypotheses such as mitochondrial dysfunction, inflammation, oxidative stress, and dysfunction of the ubiquitin-proteasome system, in the pathogenesis of neurodegenerative diseases. Therefore, pathogenic effects of the dopamine quinone have recently focused on dopaminergic neuron-specific oxidative stress. In this article, we primarily review recent studies on the pathogenicity of quinone formation, in addition to several neuroprotective approaches against dopamine quinone-induced dysfunction of dopaminergic neurons.

DOI： 10.18926/AMO/30980

Web of Science

researchmap

Nonsteroidal anti-inflammatory drugs in experimental parkinsonian models and Parkinson's disease Reviewed

Masato Asanuma, Ikuko Miyazaki

Current Pharmacutical Design 14 ( 14 ) 1428 - 1434 2008.5

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：BENTHAM SCIENCE PUBL LTD

A number of experimental studies using parkinsonian models have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) have neuroprotective properties against dopaminergic neurotoxicity not only by their cyclooxygenase-inhibiting effect but also by other specific properties or some unknown pharmacological effects. This article reviews heterogeneous pharmacological properties of NSAIDs including inhibitory effect against nitric oxide synthesis, agonistic action for peroxisome proliferator-activated receptor or possible suppressive effects against dopamine quinone generation, and also reviews their neuroprotective effects in the experimental parkinsonian models and pathogenesis of Parkinson's disease. Several epidemiological studies recently clarified that the use of nonaspirin NSAIDs but not aspirin was associated with a lower prevalence of Parkinson's disease, in contrast with neuroprotective effects of aspirin in the experimental studies. It also discusses the discrepancy between results in the experimental parkinsonian models and epidemiological data in prevalence of Parkinson's disease on the effects of NSAIDs.

DOI： 10.2174/138161208784480153

Web of Science

researchmap

Specific induction of PAG608 in cranial and spinal motor neurons of L-DOPA-treated parkinsonian rats Reviewed

Masako Shimizu, Ikuko Miyazaki, Youichirou Higashi, Maria J. Eslava-Alva, Francisco J. Diaz-Corrales, Masato Asanuma, Norio Ogawa

Neuroscience Research 60 ( 4 ) 355 - 363 2008.4

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

We identified p53-activated gene 608 (PAG608) as a specifically induced gene in striatal tissue of L-DOPA (100 mg/kg)-injected hemi-parkinsonian rats using differential display assay. In the present study, we further examined morphological distribution of PAG608 in the central nervous system of L-DOPA-treated hemi-parkinsonian rats. PAG608 expression was markedly induced in fibers and neuronal cells of the lateral globus pallidus and reticular thalamic nucleus adjacent to internal capsule, specifically in the parkinsonian side of L-DOPA-treated models. The protein was also constitutively expressed in motor neurons specifically in either side of the pontine nucleus and motor nuclei of trigeminal and facial nerves. Furthermore, L-DOPA-induced PAG608 expression on motor neurons in the contralateral side of the ventral horn of the spinal cord and the lateral corticospinal tract without cell loss. The specific induction of PAG608 6-48 h after L-DOPA injection in the extrapyramidal tracts, pyramidal tracts and corresponding lower motor neurons of the spinal cords suggests its involvement in molecular events in stimulated motor neurons. Taken together with the constitutive expression of PAG608 in the motor nuclei of cranial nerves, PAG608 may be a useful marker of stressed or activated lower motor neurons. © 2007 Elsevier Ireland Ltd and the Japan Neuroscience Society.

DOI： 10.1016/j.neures.2007.12.006

Increased susceptibility to oxidant-mediated tissue injury and peritoneal fibrosis in acatalasemic mice Reviewed

Naomi Fukuoka, Hitoshi Sugiyama, Tatsuyuki Inoue, Yoko Kikumoto, Kei-ichi Takiue, Hiroshi Morinaga, Kazushi Nakao, Yohei Maeshima, Masato Asanuma, Da-Hong Wang, Keiki Ogino, Noriyoshi Masuoka, Hirofumi Makino

American Journal of Nephrology 28 ( 4 ) 661 - 668 2008.4

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Background: Peritoneal fibrosis is a major complication leading to the loss of peritoneal function in patients undergoing peritoneal dialysis. However, the effect of catalase depletion on peritoneal fibrosis has not yet been investigated. Methods: The impact of catalase deficiency on progressive peritoneal fibrosis has been studied in homozygous acatalasemic mutant mice or control wild-type mice by intraperitoneal injection of chlorhexidine gluconate (CG) every other day for 14 days. Results: The CG injections resulted in a thicker peritoneal membrane, reflecting peritoneal fibrosis with accumulation of interstitial type I collagen, peritoneal deposition of lipid peroxidation products (4-hydroxy-2-nonenal and 4-hydroxy-2-hexenal), and an elevated level of 8-hydroxy-2'-deoxyguanosine in peritoneal fluid in both mouse groups on day 14. The extent of these changes, however, was significantly higher in acatalasemic mice than in wild-type mice. The level of catalase activity remained low in the acatalasemic peritoneum without the compensatory upregulation of glutathione peroxidase, but with an insufficient upregulation of superoxide dismutase activity in CG-injected mice. Conclusions: Acatalasemia, therefore, exacerbates oxidant tissue injury and induces the peritoneum to develop irreversible fibrosis which is the most important complication of peritoneal dialysis. This study suggests that catalase plays a crucial role in the defense against oxidant-mediated peritoneal injury in a mouse peritoneal fibrosis model. Copyright (C) 2008 S. Karger AG, Basel.

DOI： 10.1159/000121357

Web of Science

researchmap

Protective effects of interferon-gamma against methamphetamine-induced neurotoxicity Reviewed

Hiroaki Hozumi, Masato Asanuma, Ikuko Miyazaki, Saki Fukuoka, Yuri Kikkawa, Naotaka Kimoto, Yoshihisa Kitamura, Toshiaki Sendo, Taizo Kita, Yutaka Gomita

Toxicology Letters 177 ( 2 ) 123 - 129 2008.3

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Repeated injections of methamphetamine (METH) cause degeneration of striatal dopaminergic nerve terminals. In the present study, we examined the effects of interferon-gamma (IFN-gamma) on METH-induced striatal neurotoxicity in mice. Intraperitoneal injection of IFN-gamma before METH injection significantly prevented METH-induced reduction of striatal dopamine transporter (DAT)-positive signals and hyperthermia. Furthermore, intracerebroventricular injection of IFN-gamma before METH treatment markedly prevented METH-induced reduction of DAT. Interestingly, central IFN-gamma injection had no effect on METH-induced hyperthermia. In addition, IFN-gamma injected centrally after METH treatment, but not systemically, 1 h after the final METH injection significantly protected against METH-induced neurotoxicity. Our results suggest that IFN-gamma injected systemically or its related molecule protects against METH-induced neurotoxicity through intracerebral molecular pathways, while it can prevent METH-induced hyperthermia through different molecular events. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.toxlet.2008.01.005

Web of Science

researchmap

The roles of amino acid residues at positions 216 and 219 in the structural stability and metabolic functions of rat cytochrome P450 2D1 and 2D2 Reviewed

Shizuo Narimatsu, Kimio Kiryu, Rei Yonemoto, Manabu Yoshino, Mitsuko Kobatake, Daichi Kazamori, Saori Hagino, Kazufumi Masuda, Takashi Katsu, Masato Asanuma, Takuya Kumamoto, Tsutomu Ishikawa, Yoshihiko Funae, Shigeru Yamano, Nobumitsu Hanioka, Shinsaku Naito

Chemico-Biological Interactions 172 ( 1 ) 11 - 21 2008.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

We examined the effects of the mutual substitution of amino acid residues at positions 216 and 219 between rat CYP2D1 and CYP2D2 on their microsomal contents and enzymatic functions using a yeast cell expression system and 1-metloxy-N,N- diisopropyltryptamine (5-MeO-DIPT) as a substrate. CYP2D1 has amino acid residues, leucine and valine, at positions of 216 and 219, respectively, whereas CYP2D2 has phenylalanine and aspartic acid at the same positions. In reduced carbon monoxide-difference spectroscopic analysis, the substitution of Asp-219 of CYP2D2 by valine markedly increased a peak at 450 nm and concomitantly decreased a peak at 420 nm, while the replacement of Phe-216 of CYP2D2 with leucine gave no observable change. The double substitution of Phe-216 and Asp-219 by leucine and valine, respectively, yielded a typical CYP spectrum. The substitution of Val-219 of CYP2D1 by aspartic acid decreased the CYP content to one-half, whereas the replacement of Leu-216 with phenylalanine did not have any effect. The double substitution of Leu-216 and Val-219 of CYP2D1 by phenylalanine and aspartic acid, respectively, diminished the CYP content by 90%. CYP2D1 catalyzed both 5-MeO-DIPT N-deisopropylation and O-demethylation at relatively low levels, while CYP2D2 catalyzed 5-MeO-DIPT O-demethylation efficiently. The substitution of the amino acid at position 216 substantially increased 5-MeO-DIPT oxidation activities of the two CYP2D enzymes. The replacement of the amino acid at position 219 increased the 5-MeO-DIPT O- and N-dealkylation activities of CYP2D1, whereas it decreased the 5-MeO-DIPT O-demethylation activity of CYP2D2. These results indicate that amino acid residues at positions 216 and 219 have important roles in the enzymatic functions of rat CYPD1 and CYP2D2. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.cbi.2007.11.010

Web of Science

researchmap

　 PREV - NEXT 　

< ASANUMA Masato >

Papers - ASANUMA Masato