Analysis of the metabolism of haloperidol (HP) and its neurotoxic pyridinium metabolite (HPP+) in patients with drug-induced parkinsonism.
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Adult↗
Biomedical subjects
E Yoshihara
Publications and source records attributed to E Yoshihara.
The effects of the ALDH2*1/2, CYP2E1 C1/C2 and C/D genotypes on blood ethanol elimination.
The effects of CYP2E1 genotypes on the blood ethanol and acetaldehyde levels were investigated in a pair of Japanese volunteers whose ADH2, ADH3 and ALDH2 genotypes were identical but whose CYP2E1 genotypes were different. In the same way, the effects of ALDH2 and ADH2 on the ethanol elimination kinetics were also studied. The predicting 95% confidence bounds determined on regression analysis of the data suggested that after venous injection of ethanol, the blood ethanol and acetaldehyde concentrations in a volunteer normal homozygous for ALDH2 (ALDH2*1/1) were lower than in a heterozygous one (ALDH2*1/2). Also, the blood ethanol and acetaldehyde concentrations in a volunteer with the c2 and C alleles of CYP2E1 (c1/c2 and C/D) were lower than in one without the c2 and C alleles (c1/c1 and D/D). However, there were no significant differences in the blood ethanol and acetaldehyde concentrations between volunteers with ADH2*1 (ADH2*1/1) and without ADH2*1 (ADH2*1/2).
Acetaldehyde↗
The human serotonin receptor gene (HTR2) MspI polymorphism in Japanese schizophrenic and alcoholic patients.
Epidemiological and genetic studies of alcoholism and schizophrenia have been performed, and in this study, the human serotonin receptor (HTR2) polymorphism was examined in 75 alcoholics and 31 schizophrenic patients. We found that there might not be a significant difference between these psychiatric disease patients and controls in the frequency of the C1/C2 HTR2 gene (MspI polymorphism). The results suggest that the human HTR2 MspI polymorphism might not be associated with a risk factor for developing alcohol dependence or susceptibility to schizophrenia. It is possible that there may be a racial difference in the frequency of the C1/C2 gene between Japanese and Caucasians. Further studies are required to determine whether or not the novel serotonin receptor polymorphism reflects the pathogenesis of alcoholism or schizophrenia.
Alcoholism↗
Mechanism of relaxant response to papaverine on the smooth muscle of non-pregnant rat uterus.
In the present paper, we examined a mechanism of the papaverine induced relaxation in the smooth muscle of non-pregnant rat uterus. The hyperosmotic 65 mM KCl (H-65K+)-or oxytocin-induced contraction in the uterus was inhibited by an addition of papaverine in a concentration-dependent manner. Papaverine did not increase both cAMP and cGMP contents in the uterus in the presence of H-65K+ or oxytocin. In fura 2 loaded muscles, papaverine did not affect an increase of [Ca2+]i level by high K+ or oxytocin. In permeabilized muscles, papaverine had no effect on the Ca2+-induced contraction. H-65K+ and oxytocin increased the rate of oxygen consumption 1.8 and 1.5 times higher than that in the resting condition, respectively. The increase of oxygen consumption in the H-65K+ or oxytocin was significantly inhibited by papaverine (1-100 microM). These results suggested that papaverine inhibits smooth muscle contraction mainly by inhibition of mitochondrial respiration in rat uterus as well as guinea pig ileum, which shows a highly spontaneous activity and a highly metabolic dependency of a contraction.
Animals↗
Interplay between the efflux pump and the outer membrane permeability barrier in fluorescent dye accumulation in Pseudomonas aeruginosa.
Pseudomonas aeruginosa encodes three types of xenobiotic efflux pumps, MexAB-OprM, MexCD-OprJ, and MexEF-OprN, which are regulated by the nalB, nfxB, and nfxC genes, respectively, and their high expression renders the cells resistant to multiple species of antibiotics. We evaluated the role of the outer membrane permeability barrier and the efflux pump in lowering the intracellular concentration of fluorescent probes. The wild-type, nalB, nfxB, and nfxC strains with an intact outer membrane showed equally high capability in draining out intracellular fluorescent dye, 2-(4-dimethylaminostyryl)-1-ethylpyridinium and ethidium bromide. When the outer membrane barrier was dismantled by the EDTA treatment, wild-type, nfxC, nfxB, and nalB strains showed significantly different levels of dye accumulation. The polymyxin B-treated cells showed an even more pronounced difference in dye accumulation among the nfxC, nfxB, and nalB mutants. We concluded from these results that the xenobiotic extrusion pumps interplay with the outer membrane permeability barrier in lowering the intracellular substrate concentration. Among three extrusion pumps in P. aeruginosa, MexAB-OprM was the most efficient, followed by MexCD-OprJ and MexEF-OprN pumps for the fluorescent dye extrusion.
Bacterial Outer Membrane Proteins↗
Molecular cloning and characterization of the oprQ gene coding for outer membrane protein OprE3 of Pseudomonas aeruginosa.
We cloned and characterized the oprQ gene coding for outer membrane protein OprE3 of Pseudomonas aeruginosa PAO1. The oprQ gene was composed of 1,275 base pairs including a sequence encoding for the signal sequence and a mature protein with a Mr of 44,602. Computer-aided alignment and hydropathy analyses of the predicted amino acid sequences suggested that OprE3 is a transmembrane protein homologous to outer membrane proteins of P. aeruginosa such as OprD2 (OprD) porin and OprE1 (OprE) porin. Susceptibility to several antibiotics of the strains lacking or overproducing OprE3 was indistinguishable from that of the wild-type strain, suggesting that OprE3 is unlikely involved in the diffusion of carbapenems and other beta-lactam antibiotics.
Amino Acid Sequence↗
CYP2D6 HhaI genotype and the neuroleptic malignant syndrome.
To investigate the relationship between CYP2D6 genotypes (reported to be associated with the susceptibilities to Parkinson's disease and multisystem atrophy) and the possible susceptibility to neuroleptic malignant syndrome (NMS) and subacute myelo-optico-neuropathy (SMON), we analyzed the CYP2D6 gene by polymerase chain reaction and restriction fragment length polymorphism in Japanese schizophrenia patients with a history of NMS. There was no significant difference in the frequency of the poor metabolizer genotype of CYP2D6 between the cases with a history of NMS and controls (p > 0.05). The frequency of the mutation located at the HhaI site in exon 6 of CYP2D6 in the cases was higher, but not significantly (p > 0.05; the mutated allele frequency was 0.25), than that in the controls, schizophrenia patients without NMS (0.11) and healthy controls (0.09). The frequency (0.10) of the HhaI mutation type in patients with a diagnosis of SMON was also not significantly higher than in healthy controls. These results suggest that the poor metabolizer and HhaI polymorphism of CYP2D6 may not be a useful molecular marker for predicting the onset of NMS and SMON.
Adult↗
[Relationship between alcoholism and HTR2 MspI polymorphism].
We investigated the human serotonin receptor, HTR2 genotype among 73 alcoholics. We found that there might not be a significant difference between alcoholics and controls in the frequency of HTR2 C1/C2 gene (MspI polymorphism). This result suggested that the HTR2 C1/C2 gene might not be associated with the risk factor for developing alcohol dependence. Further studies are required to determine whether or not a novel serotonin receptor polymorphism reflects pathogenesis of alcoholism.
Adult↗
Identification of the catalytic triad of the protein D2 protease in Pseudomonas aeruginosa.
We reported recently that protein D2 (OprD) porin of Pseudomonas aeruginosa bears protease activity (FEBS Letters 394, 179-182, 1996). To identify the catalytic residues of OprD, we introduced the site-directed mutations replacing the putative catalytic triad His156, Asp208, and Ser296 with glutamine, asparagine, and alanine, respectively. The OprD proteins purified from the chromosomal oprD-deficient mutants harboring the plasmids encoding the site-directed mutations showed protease activity less than 0.1% of that of the wild-type OprD. These site-directed mutageneses caused undetectable changes in the pore-forming activity of OprD as measured by single-channel conductance by the planar lipid bilayer. The minimum inhibitory concentration of imipenem in mutants having the replaced catalytic triads was identical with that in the wild-type strain. On the other hand, introduction of the mutation at His367 replacing with glutamine, the site that is supposed to be unrelated to the catalytic sites, showed the unchanged protease activity. These results unequivocally demonstrate that OprD is the protease bearing porin and catalyzes the reaction at His156, Asp208, and Ser296 residues.
Alanine↗
cDNA cloning of a heterogeneous two-chain anticoagulant protein IX-bp.
IX-bp and IX/X-bp are heterogeneous two-chain anticoagulant proteins isolated from the venom of habu snake, Trimeresurus flavoviridis. The amino acid sequence of one (B chain) of their two chains is identical. We recently reported the cloning of cDNA encoding the B chain and that of the A chain of IX/X-bp. Here, we report the isolation and characterization of cDNA clones encoding the A chain of IX-bp. The 697-bp sequence showed a putative ORF capable of encoding a 152-amino-acid protein containing a 23-amino-acid signal peptide. The overall amino acid sequence identity between the pre-A chain of IX-bp and that of IX/X-bp is 84%, whereas the cDNA sequence identity of the two ORFs is 91% indicating that habu snake acquired the variety of venom proteins by efficient mutations of antonymous sites.
Amino Acid Sequence↗
[Properties of extracellular products produced by group A streptococci isolated from patients with streptococcal toxic shock syndrome].
Extracellular products of group A streptococci isolated from patients with streptococcal toxic shock syndrome (STSS) were examined. The outline of the discussion of the 3 products are as follows; streptolysin O (SLO), proteinase and erythrogenic toxin. SLO and proteinase showed a relatively large amount of products more than erythrogenic toxin. SLO produced by group A streptococci isolated from the patient with STSS had an isoelectric point (pI) of 6.0 and a molecular weight of 64,000 and showed hemolytic activity in the presence of 2-mercaptoethanol (2-ME). Furthermore, the hemolytic activities of all components were inhibited by gamma-globulin and cholesterol. Proteinase had pIs of 8.7 and 8.9, and a molecular weight of 21,000. These data suggest that STSS clinical criteria probably reflects a characteristic of a large amount of products of individual S. pyogenes isolates.
Bacterial Proteins↗
[Properties of extracellular products produced by group A streptococci isolated from patient with streptococcal toxic shock syndrome].
Extracellular products of group A streptococci isolated from patients with streptococcal toxic shock syndrome (STSS) examined. The outline of discussion of the 4 products are as follows; Products were streptolysin O (SLO), proteinase, erythrogenic toxin and DNase. SLO showed a large amount of products more than proteinase, erythrogenic toxin and DNase. It should not be concluded that there is a large amount of SLO in the isolated strains from patients with STSS. SLO produced by group A streptococci isolated from the patient with STSS has an isoelectric point (pI) of 6.0 and a molecular weight of 64,000 and shows a hemolytic activity in the presence of 2 mercaptoethanol (2-ME). Furthermore, the hemolytic activities of all components were inhibited by gamma-globulin and cholesterol. These results indicated that all component with hemolytic activity are SLO. These data suggest that STSS does not make up a single syndrome but, rather, that the multiple STSS clinical criteria probably reflects a different characteristic of individual S. pyogenes isolates.
Bacterial Proteins↗
Protein D2 porin of the Pseudomonas aeruginosa outer membrane bears the protease activity.
We report here our discovery that protein D2 of the outer membrane of Pseudomonas aeruginosa is a novel porin bearing protease activity. Homogeneously purified protein D2 hydrolyzed several synthetic peptides according to the Michaelis-Menten kinetics. A specific serine protease inhibitor, diisopropyl fluorophosphate (DFP), inactivated the protease activity and [3H]DFP covalently labeled protein D2. We tested the effect of two monoclonal antibodies raised against protein D2 on the protease activity. One antibody lowered the protease activity to about 20%, while the other enhanced it to about 300% of that without antibody. In addition, the fractions derived from the outer membrane of the protein D2-deficient mutants showed negligible protease activity, whereas similarly fractionated outer membrane proteins of the protein D2-positive parent strain showed strong protease activity.
Amino Acid Sequence↗
[Properties of a hemolysin produced by group B streptococci].
The hemolysin produced by group B streptococci (GBH) has an isoelectric point (pI) of 5.8 and it shows a hemolytic activity in the absence of 2-mercaptoethanol (2-ME). The hemolytic activities of GBH were compared to that of streptolysin O (SLO) and streptolysin S (SLS). These hemolysins differed with respect to the binding and release of hemoglobin (Hb). GBH was bound to phospholipids on the membranes of target erythrocytes, followed by the gentle release of K+ and slow Hb release without lag time. Incontrast SLO released Hb as rapidly as K+. GBH induced hemolysis was inhibited by the addition of 30 mM raffinose. These results indicate that the effective diameter of the pores formed by GBH was about 1.1 nm. GBH showed a lower hemolytic efficiency than SLO, reflecting the fact that these hemolysins destroy erythrocytes by a different mechanism. Intracellular K+ and Hb were released at a different rate in GBH treated cells, indicating that a colloid-osmotic process is involved in the lytic mechanism.
Bacterial Proteins↗
Blood coagulation factor IX-binding protein from the venom of Trimeresurus flavoviridis: purification and characterization.
The coagulation factor IX/factor X-binding protein (IX/X-bp) from the venom of Trimeresurus flavoviridis is a heterogeneous two-chain protein, and the structure of each chain is similar to that of the carbohydrate-recognition domain of C-type lectins, such as asialoglycoprotein receptors, pancreatic stone protein, and the Fc epsilon receptor for immunoglobulin E. Analysis of the binding properties of IX/X-bp revealed that it binds to the gamma-carboxyglutamic acid (Gla)-containing domains of factors IX and X [Atoda, H. et al. (1994) Eur. J. Biochem. 224, 703-708]. In the present study, we isolated another anticoagulant protein that binds to factor IX but is not to factor X. This protein, designated IX-bp, inhibited factor IXa-induced clotting but not factor Xa-induced clotting, whereas IX/X-bp inhibits both. The concentration of IX-bp for half-maximal binding to solid-phase bovine factor IX was 0.4 nM whereas IX-bp did not bind to factor X even at 40 nM. The binding of IX-bp to solid-phase factor IX was inhibited by the addition of Gla-domain peptide of factor IX, indicating that IX-bp binds to the Gla-domain region of factor IX. IX-bp had two Ca(2+)-binding sites with different affinities for Ca2+ ions. At pH 7.5, the apparent Kd values for these sites were 14 and 130 microM, respectively. IX-bp was a two-chain protein (27.5-kDa band before reduction and 16.8- and 15.7-kDa bands after reduction on SDS-PAGE) and it reacted with immunoglobulin G against IX/X-bp. The complete amino acid sequence of IX-bp was determined. The 16.8-kDa chain (A chain) of IX-bp consisted of 129 residues, of which 19 were different from those in the A chain of IX/X-bp (129 residues). The sequence of the 15.7-kDa chain (B chain) was identical to that of the B chain of IX/X-bp (123 residues). We conclude that IX-bp is a protein that is structurally similar to but functionally different from IX/X-bp. The difference of binding specificity between IX-bp and IX/X-bp presumably arises from the sequence differences in the A chains.
Amino Acid Sequence↗
[Properties of a hemolysin produced by group C streptococci isolated from hemolytic streptococcal infection in formosan squirrels].
The hemolysin produced by group C streptococci (GCH) has an isoelectric point (pI) of 5.6 and a molecular weight of 32,000 and shows hemolytic activity in the absence of 2-mercaptoethanol (2-ME). The hemolytic activity of GCH was compared to that of streptolysin S (SLS). These hemolysins did not differ with respect to the binding and release of hemoglobin (Hb). GCH was bound to phospholipids on the membranes of target erythrocytes, followed by the rapid released of K+ and slow Hb release after a relatively long lag time. GCH showed a lower hemolytic efficiency than SLS, reflecting the fact that these hemolysins destroy erythrocytes by slightly different mechanisms.
Animals↗
Calcium ion-mediated opening of the channel gate in the Pseudomonas aeruginosa porin.
The gate-forming domain of protein D2 (OprD2) in the outer membrane of Pseudomonas aeruginosa contains an amino acid sequence homologous to the calcium-binding site of the myosin light chain. This observation lets us to test the effect of Ca2+ on the channel function of OprD2. The diffusion rate of p-nitrophenyl phosphate (PNPP) through OprD2 was 2.3 times higher in the presence of mM order of Ca2+, but not Mg2+ or Mn2+. Concomitantly, the intrinsic fluorescence emission of OprD2 became about 10% lower in the presence of Ca2+. As the proteolytic cleavage of the gate-forming domain of OprD2 results the channel activity about 7 times higher, we tested the effect of Ca2+ on the solute permeability through the trypsin-treated OprD2. The diffusion rate of PNPP in the trypsin-treated OprD2 appeared to be nearly identical in the presence and absence of Ca2+. The result suggests that Ca2+ activates the OprD2 channel exerting its effect on the gate-forming domain.
Bacterial Outer Membrane Proteins↗
Separation of gate- and channel-forming domains in the pore-forming protein of the outer membrane of Pseudomonas aeruginosa.
The domains of the pore-forming protein responsible for the gate and channel formations were separated and identified in the outer membrane of Pseudomonas aeruginosa. The proteolytic cleavage of the 46K channel protein, protein D2, yielded two major domains with apparent M(r) of 27K and 19K. We identified the 27K polypeptide to be the channel-forming domain by an in vitro permeability assay. The channel size of purified 27K domain was indistinguishable from that of native protein D2. Degradation of the 19K domain into small subfragments increases the channel activity about ten times suggesting that the 19K polypeptide forms the gate or cap.
Bacterial Outer Membrane Proteins↗