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31.
Objective: The present study was conducted to identify in vitro the cytochrome P450(CYP) isoform involved in the metabolic conversion
of reduced haloperidol to haloperidol using microsomes derived from human AHH-1 TK +/− cells expressing human cytochrome P450s.
The inhibitory and/or stimulatory effects of reduced haloperidol or haloperidol on CYP2D6-catalyzed carteolol 8-hydroxylase
activity were also investigated.
Results: The CYP isoform involved in the oxidation of reduced haloperidol to haloperidol was CYP3A4. CYP1A1, 1A2, 2A6, 2B6, 2C8,
2C9, 2C19, 2D6, and 2E1 were not involved in the oxidation. The kM value for the CYP3A4 expressed in the cells was 69.7 μmol · l−1, and the Vmax was 4.87 pmol · min−1 · pmol−1 P450. Troleandomycin, a relatively selective probe for CYP3A enzymes, inhibited the CYP3A4-mediated oxidation of reduced
haloperidol in a dose-dependent manner. Quinidine and sparteine competitively inhibited the oxidative reaction with a ki value of 24.9 and 1390 μmol · l−1, respectively. Carteolol 8-hydroxylase activity, which is a selective reaction probe for CYP2D6 activity, was inhibited by
reduced haloperidol with a ki value of 4.3 μmol · l−1. Haloperidol stimulated the CYP2D6-mediated carteolol 8-hydroxylase activity with an optimum concentration of 1 μmol · l−1, whereas higher concentrations of the compound (>10 μmol · l−1) inhibited the hydroxylase activity.
Conclusion: It was concluded that CYP3A4, not CYP2D6, is the principal isoform of cytochrome P450 involved in the metabolic conversion
of reduced haloperidol to haloperidol. It was further found that reduced haloperidol is a substrate of CYP3A4 and an inhibitor
of CYP2D6, and that haloperidol has both stimulatory and inhibitory effects on CYP2D6 activity.
Received: 10 April 1997 / Accepted in revised form: 16 December 1997 相似文献
32.
Takio Kitazawa Katsunori Kudo Mitsue Ishigami Hidenari Furuhashi Kyosuke Temma Hiroshi Kondo 《Naunyn-Schmiedeberg's archives of pharmacology》1988,338(1):68-73
Summary The participation of substance P in the noncholinergic contraction induced by transmural stimulation (TMS) of the carp intestinal bulb was examined. In the presence of atropine, substance P caused the contraction of carp intestinal bulb smooth muscle in a concentration dependent manner (1 nmol/1 – 1 mol/l). The EC50 value was 28 ± 7 nmol/l (n = 6). Substance P-induced desensitization (1 mol/l for 15 min), decreased the response to substance P and the atropine-resistant contraction induced by TMS (20 Hz) selectively. In contrast, in the absence of atropine, the contraction induced by TMS (20 Hz) was slightly attenuated with the substance P-induced desensitization. The acid extract obtained from the carp intestinal bulb contained a smooth muscle excitatory material whose pharmacological properties were consistent with those of substance P. The present results indicate that a substance P-like peptide is present in the carp intestinal bulb which is involved in the non-cholinergic contraction induced by TMS.Send offprint requests to T. Kitazawa at the above address 相似文献
33.
Satoko Arai Yuka Shinohara Yasuyuki Kato Satoshi Hirano Atsuto Yoshizawa Masaaki Hojyo Nobuyuki Kobayashi Haruhito Sugiyama Koichiro Kudo 《Arerugī》2007,56(10):1293-1297
A 51-year-old man was admitted to our hospital with fever, dry cough and dyspnea. He had taken minocycline for 11 days because of urinary tract infection. Chest X-ray on admission showed diffuse reticular shadows in bilateral lung fields with bilateral pleural effusion. Cessation of minocycline led to spontaneous improvement of symptoms and radiographic findings. The lymphocyte stimulation test for minocycline with peripheral blood and pleural effusion were negative. After provocation test with minocycline, he developed fever and dry cough and bilateral ground glass opacity appeared on his chest X-ray. He was diagnosed as minocycline-induced pneumonitis and recovered rapidly following corticosteroid therapy. 相似文献
34.
Yuzo Okumura Jiro Kudo Tohru Ikuta Satoshi Kurokawa Hiromi Ishibashi Hideo Okubo 《Inflammation》1985,9(2):211-219
The effects of
1-antitrypsin (
1,-AT),
1,-acid glycoprotein (
1AGP), and haptoglobin (Hp), the main constituents of-globulin and which belong to acute phase proteins, on NK activity were examined using K562 cells as the NK target cells. Among the three proteins,
1,-AT and
1AGP had inhibitory effects on NK activity for fast target K562 cells. The,-AT preparations having the same protein concentration and a different trypsin inhibitory capacity (TIC) had an equal effect. Although
1AT and
1,-AGP equally reduced the NK activity, the mechanism involved in the reduction differed, in that the effect of
1,-AT directed toward NK cells reduced their binding capacity with the target cells,
1,-AGP probably interacts with a cytotoxic factor secreted from NK cells following effector-target interaction. These studies suggest that each of the acute-phase proteins, which increase following inflammation, inhibits NK cell function by two distinct mechanisms. 相似文献
35.
Networks generating locomotor-like rhythmic motor activity are formed during the last week of the fetal period in the rat spinal cord. We investigated the coordinated rhythmic motor activity induced in transverse slice preparations of the lumbar spinal cord taken from fetal rats as early as embryonic day (E) 16.5. In slices as thin as 100 microm, bath-application of 5-hydroxytryptamine (5-HT) induced rhythmic [Ca(2+)](i) elevations in motoneurons labeled with Calcium Green-1 dextran. The rhythmic [Ca(2+)](i) elevations were similar in frequency to that in the intact lumbar spinal cord, although there was no temporal correlation between the activity in the left and right sides of 100-microm slices. Such rhythmic [Ca(2+)](i) elevations were observed in the slices taken from all lumbar segments. Moreover, the rhythmic activity was abolished by simultaneous blockade of glutamate, glycine, and GABA(A) receptors, indicating that synaptic transmission mediated by these receptors is important for the generation of the rhythm in these slices. Synchronous rhythmic activity between the left-right sides was found in slices thicker than 200 microm taken from any segmental level of the lumbar spinal cord. In these preparations, commissural neurons were activated synchronously with ipsilateral motoneurons. These results indicate that the neuronal networks sufficient to generate coordinated rhythmic activity are contained in one-half of a single lumbar segment at E16.5. Such spinal cord slices are a promising experimental model to investigate the neuronal mechanisms and the development of rhythm generation in the spinal cord. 相似文献
36.
Lymphokine activity production in graft-versus-host reactions across minor histocompatibility antigen barriers. 总被引:1,自引:0,他引:1
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M Hirokawa H Takatsu A Ohshima A Chubachi K Kudo H Niitsu T Takahashi K Yoshida A B Miura 《Clinical and experimental immunology》1989,77(3):434-439
Activated T cells responding to murine minor histocompatibility antigens (HA) were characterized according to the patterns of lymphokine activity production. Although B10.D2/nSN and BALB/c are mutually non-reactive in mixed lymphocyte reaction (MLR), graft-versus-host reaction (GVHR) can be induced by the injection of a large amount of B10.D2/nSN lymphoid cells into irradiated BALB/c recipient mice. Spleen cells from such GVHR mice spontaneously produced interleukin 3 (IL-3)-dependent cell-stimulating activity in cultures, but did not produce interleukin 2 (IL-2). Normal B10.D2/nSN spleen cells also produced IL-3-like activity, but not IL-2 in MLR supernatants, in response to irradiated BALB/c splenocytes. In addition, B-cell stimulatory factor-1 (BSF-1)/interleukin 4 (IL-4) and colony-stimulating factor (CSF) activity were detected in MLR supernatants. The properties of the produced lymphokine activities were similar to those produced in syngeneic transplant mice and syngeneic MLR, but a difference in the time course of lymphokine production existed between GVHR and syngeneic transplant mice. These results indicate that T cells may be activated in vivo in allogeneic transplantation when the donor and the recipient are matched for major HA, and are non-reactive in MLR. Also, the character of lymphokine-producing T cells activated by minor HA may not be qualitatively different from those responding to irradiated syngeneic cells. 相似文献
37.
The primary function of neurons is to integrate synaptic inputs and to transmit the results to other cells. Recent studies with somatic whole-cell recordings have shown that separate excitatory inputs to hippocampal or cortical pyramidal neurons are summated non-linearly. In the present study, we examined how postsynaptic potentials (PSPs) are summated along the dendrites employing fast optical voltage imaging techniques. Rat hippocampal slices were stained with a fluorescent voltage-sensitive dye (JPW1114) and optical signals were monitored with a 16 x 16 photodiode array system. Two independent input pathways were stimulated individually or in pairs through glass electrodes such that different locations of the dendrites received separate synaptic inputs. We found that (1) the summation of PSPs was sub-linear along the entirety of dendrites, (2) the blockade of GABA(A) receptors suppressed sub-linearity and (3) further blockade of GABA(B) receptors suppressed sub-linearity of the summation of separate inputs on apical dendrites. Our study demonstrates that pyramidal neurons integrate PSPs linearly along the entirety of dendrites; moreover, GABAergic inputs are responsible for maintaining sub-linear summation in CA1 pyramidal neurons. 相似文献
38.
Are cerebrovascular factors involved in Alzheimer's disease? 总被引:13,自引:0,他引:13
Kudo T Imaizumi K Tanimukai H Katayama T Sato N Nakamura Y Tanaka T Kashiwagi Y Jinno Y Tohyama M Takeda M 《Neurobiology of aging》2000,21(2):215-224
Recent epidemiological studies have shown that vascular risk factors may be involved in Alzheimer's disease (AD) as well as dementia in general. To investigate the relation between a vascular disorder and AD pathology, current criteria are defective because most depend on exclusion of a cerebrovascular disorder. Epidemiological studies have indicated the possibilities that arteriosclerosis, abnormal blood pressure, diabetes mellitus and smoking may be related to the pathogenesis of AD. As for the mechanism that vascular disorders influence AD, it is presumed that amyloid deposition may be caused by a vascular disorder. Alternatively, a vascular event may cause progression of subclinical AD to a clinical stage. Insulin resistance and apolipoprotein E may also be involved in these mechanisms. Our studies show that ischemia-induced the Alzheimer-associated gene presenilin 1 (PS1) and endoplasmic reticulum-stress, generated from a vascular disorder, may unmask clinical AD symptoms caused by presenilin mutation, suggesting that a vascular factor might be involved in the onset of familial AD. 相似文献
39.
M Tsukamura C Komatsuzaki R Sakai K Kaneda T Kudo A Seino 《Journal of clinical microbiology》1988,26(1):155-157
Rhodococcus sputi caused tuberculosislike lymphadenitis of mesenteric lymph nodes in swine. This is the first study reporting that R. sputi can be a pathogen in swine. 相似文献
40.