Cathepsin D polymorphism not associated with Alzheimer's disease in Japanese.
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Aged↗
Biomedical subjects
S Higuchi
Publications and source records attributed to S Higuchi.
Identification of rat urinary and biliary metabolites of esonarimod, a novel antirheumatic drug, using liquid chromatography/electrospray ionization tandem mass spectrometry with postcolumn addition of 2-(2-methoxyethoxy)ethanol, a signal-enhancing modifier.
The biotransformation of esonarimod (KE-298) [(+/-)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid], a new antirheumatic drug, was investigated in rats. Urinary and biliary excretions within 24 h after oral administration of 5 mg/kg [(14)C]esonarimod accounted for 89 and 10% of the dose, respectively. Initial metabolite analysis by liquid chromatography/electrospray ionization tandem mass spectrometry with negative ion mode, in which a mobile phase of 20 mM ammonium acetate (pH 4.6)/methanol with gradient-elution mode was used, failed to obtain any structural information on most of the metabolites due to poor sensitivity. To overcome this problem, postcolumn addition of 2-(2-methoxyethoxy)ethanol, a powerful signal-enhancing modifier, to the mobile phase was used, allowing pronounced signal enhancement and structural elucidation of urinary and biliary metabolites. The results of metabolite analysis suggested that esonarimod is predominantly biotransformed to a pharmacologically active metabolite, thiol-containing deacetyl-esonarimod (M-I), and subsequently undergoes extensive metabolism, mainly S-methylation followed by the combination of S-oxidation and oxidative conversion of the aromatic methyl group. No disulfide metabolites, such as M-I-cysteine mixed disulfide and M-I-dimer, were found in the excreta. This finding is probably evidence supporting the notion that the reactivity of the thiol moiety of M-I with macromolecules in vivo is extremely lower than that of common thiol-containing drugs.
Animals↗
Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene.
To evaluate whether mutations in the human multidrug resistance (MDR)-1 gene correlate with placental P-glycoprotein (PGP) expression, we sequenced the MDR-1 cDNA and measured PGP expression by Western blotting in 100 placentas obtained from Japanese women. Nine single nucleotide polymorphisms (SNPs) were observed with an allelic frequency of 0.005 to 0.420. Of these SNPs, G2677A (allelic frequency = 0.18) and G2677T (0.39) in exon 21 were associated with an amino acid conversion from Ala to Thr and to Ser, respectively. Sixty-one of 65 samples (93.8%), which had a C3435T allele, also had a mutant G2677(A,T) allele, suggesting an association between the two SNPs. Correlations of mutations with expression levels were observed; individuals having the G2677(A,T) and/or T-129C (p < 0.05) allele had less placental PGP. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)-based genotyping tests were developed for the detection of these SNPs. The PCR, in which genomic DNAs obtained from healthy subjects (n = 48) are used as samples, was successful. The frequency of mutations in placental cDNA was identical with that in genomic DNA. When genotype results were compared between Caucasians and Japanese, ethnic differences in the frequency of polymorphism in the MDR-1 gene were suspected. Although it remains to be determined whether these SNPs influence the pharmacokinetic and dynamic properties of clinically useful drugs that are substrates of PGP, the polymorphism of the MDR-1 gene presented here may provide useful information in in vivo study of these issues.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
[Current status, clinical characteristics and treatment of alcohol-related problems in the elderly].
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Adult↗
Dosing time-dependent tolerance of catalepsy by repetitive administration of haloperidol in mice.
To investigate the effect of repeated administration time on the development of tolerance, male ICR mice, housed under 12:12-h light/dark cycle (7:00 AM, lights on), were treated with haloperidol 4 mg/kg/day i.p. at 9:00 AM or 9:00 PM, the time nearly corresponding to the maximal or minimal catalepsy responses to a single dose, respectively, for 14 days and catalepsy responses were monitored at 1 h after administration each day. The findings indicated that, on day 1 to day 6, a greater development of tolerance was seen in the group of mice treated at 9:00 AM, and catalepsy behavior exhibited a significant difference between the two dosing times (P < 0.01). The study of D(2) receptor mRNA expression in mouse striatum revealed that the phase of D(2) receptor mRNA rhythm was similar to that of catalepsy response, with the maximum around mid-light and the minimum around mid-dark. After repeated administration, the increase in D(2) receptor mRNA levels in mice treated with haloperidol at 9:00 AM was higher than that of mice treated with haloperidol at 9:00 PM. In addition, from a [(3)H]spiperone binding study, the amount of binding site [(3)H]spiperone after repeated injection of haloperidol at 9:00 AM was greater than that after repeated injection at 9:00 PM. These findings demonstrate the importance of dosing time on the susceptibility to extrapyramidal effects and the relation of administration time to D(2) receptor change and tolerance.
Animals↗
Oxidation mechanism of 7-hydroxy-delta 8-tetrahydrocannabinol and 8-hydroxy-delta 9-tetrahydrocannabinol to the corresponding ketones by CYP3A11.
A cDNA isolated from a C57BL/6 mouse liver cDNA library had the identical nucleotide sequence in coding region with the mouse CYP3A11, and the NH(2)-terminal sequence was also identical to that of cytochrome P450 (P450) MDX-B, a microsomal alcohol oxygenase. The COS-7 cells transfected with the CYP3A11 expression vector formed 7-oxo-Delta(8)-tetrahydrocannabinol (7-oxo-Delta(8)-THC) from 7alpha- and 7beta-hydroxy-Delta(8)-THC. An immunologically related protein with P450 MDX-B was expressed in the COS-7 cell microsomes. The cell microsomes expressed CYP3A11; COS-3A11 catalyzed the oxidation of 7-hydroxy-Delta(8)-THC and 8-hydroxy-Delta(9)-THC to 7-oxo-Delta(8)-THC and 8-oxo-Delta(9)-THC, respectively, in a reconstituted system. (18)O derived from atmospheric oxygen was incorporated into about 30% of the corresponding ketones formed from 7alpha-hydroxy-Delta(8)-THC and 8beta-hydroxy-Delta(9)-THC by mouse hepatic microsomes, P450 MDX-B, and COS-3A11, although incorporation of the stable isotope into the oxidized metabolites from 7beta-hydroxy-Delta(8)-THC and 8alpha-hydroxy-Delta(9)-THC was negligible. (18)O, however, was not incorporated into 7-oxo-Delta(8)-THC formed from 7alpha-hydroxy-Delta(8)-THC by using cumene hydroperoxide instead of NADPH under (18)O(2). When (18)O-labeled 7alpha-hydroxy-Delta(8)-THC and 8beta-hydroxy-Delta(9)-THC were incubated with above enzymes under air, about 30% of the ketones formed released (18)O from a hydroxy group at the 7 and 8 positions in the course of the oxidation. These results suggest that 7alpha-hydroxy-Delta(8)-THC and 8beta-hydroxy-Delta(9)-THC may be oxidized to the corresponding ketones by CYP3A11 via a gem-diol pathway. 7beta-Hydroxy-Delta(8)-THC and 8alpha-hydroxy-Delta(9)-THC may be also converted to the ketones through a stereoselective dehydration of an enzyme-bound gem-diol rather than through a direct hydrogen extraction as a peroxy form of the enzyme.
Animals↗
Archaeal adaptation to higher temperatures revealed by genomic sequence of Thermoplasma volcanium.
The complete genomic sequence of the archaeon Thermoplasma volcanium, possessing optimum growth temperature (OGT) of 60 degrees C, is reported. By systematically comparing this genomic sequence with the other known genomic sequences of archaea, all possessing higher OGT, a number of strong correlations have been identified between characteristics of genomic organization and the OGT. With increasing OGT, in the genomic DNA, frequency of clustering purines and pyrimidines into separate dinucleotides rises (e.g., by often forming AA and TT, whereas avoiding TA and AT). Proteins coded in a genome are divided into two distinct subpopulations possessing isoelectric points in different ranges (i.e., acidic and basic), and with increasing OGT the size of the basic subpopulation becomes larger. At the metabolic level, genes coding for enzymes mediating pathways for synthesizing some coenzymes, such as heme, start missing. These findings provide insights into the design of individual genomic components, as well as principles for coordinating changes in these designs for the adaptation to new environments.
Adaptation, Physiological↗
Determination of pibutidine metabolites in human plasma by LC-MS/MS.
A novel metabolite-screening procedure for pibutidine. an H2-receptor antagonist, which uses high-performance liquid chromatography/tandem mass spectrometry (LC-MS/MS), demonstrated the presence of pibutidine and its four metabolites in plasma from volunteers who received a single dose of pibutidine hydrochloride. In order to quantitatively examine the metabolism of pibutidine, an assay based on LC-MS/MS was subsequently developed for the simultaneous determination of its metabolites in human plasma. Target analytes consisted of M-5, M-7 and M-8, which were prominently detected by the screening procedure, and M-9, which has pharmacological activity as an H2-receptor antagonist. Metabolites and their deuterated internal standards were extracted from human plasma using an Oasis HLB extraction cartridge, and chromatographed on a Monitor C18M column. No isotope effects on chromatographic retention time were observed for any deuterated compounds, which were ionized using an electrospray ionization (ESI)- interface and detected by MS/MS in the selected reaction-monitoring (SRM) mode simultaneously with the corresponding metabolites. The assay was validated over the concentration range of 0.1 to 25.6 ng ml(-1) and used to determine the plasma levels of metabolites in volunteers following oral administration of a 20-mg dose of pibutidine hydrochloride.
Area Under Curve↗
Allele association studies with SSR and SNP markers at known physical distances within a 1 Mb region embracing the ALDH2 locus in the Japanese, demonstrates linkage disequilibrium extending up to 400 kb.
There has been considerable recent debate concerning the distances over which levels of allelic association useful for genomic quantitative trait locus (QTL) scans can be detected. We have examined simple sequence repeat (SSR) polymorphisms and two single nucleotide polymorphisms (SNPs) in the region flanking the aldehyde dehydrogenase 2 locus, ALDH2, in populations of Japanese alcoholics and controls. These groups differ significantly in the allele frequencies for the functional SNP in exon XII of this gene located on chromosome 12. The results obtained with SSR markers complement recent investigations with SNPs over similar distances at the TCR alpha/delta locus. Significant allelic association with this marker could be detected for SSRs over distances up to 400 kb and over 37 kb for the SNP thereby extending the distance over which LD at this locus could be detected by an order of magnitude. Furthermore, as a proof of principle, we show that comparisons of allele frequency differences for the SSR markers in the case (alcoholics) and control populations would have detected the ALDH2 marker as a putative QTL. Extending the tests to include alleles at two or three flanking loci suggests that the power to detect QTLs through association can be enhanced significantly.
Alcohol Dehydrogenase↗
Switch of histamine receptor expression from H2 to H1 during differentiation of monocytes into macrophages.
It is known that histamine suppresses gene expression and synthesis of tumor necrosis factor alpha (TNF-alpha) induced by lipopolysaccharide (LPS) in human peripheral blood mononuclear monocytes (HPM) or alveolar macrophages via histamine H2 receptors. We investigated the effect of histamine and differentiation in macrophages on the expression and secretion of TNF-alpha, TNF-alpha-converting enzyme (TACE), and histamine H1 and H2 receptors by use of a leukemia cell line, U937, and HPM. Differentiation of U937 and HPM cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) enhanced the H1 receptor expression and rather suppressed the H2 receptor, resulting in up-regulation of the histamine-induced expression and secretion of TNF-alpha, modulated via TACE. Therefore, histamine failed to inhibit up-regulated expression of TNF-alpha induced by LPS in macrophages. The switch from H2 to H1 receptors during differentiation in the monocyte/macrophage lineage could participate in the pathogenic processes of atherosclerosis and inflammatory reactions in the arterial wall.
ADAM Proteins↗
Alpha2-macroglobulin gene polymorphisms show racial diversity and are not associated with Alzheimer's disease.
Two genetic markers of the plasma protein alpha2-macroglobulin, a 5 bp deletion/insertion at the 5' splice site of exon 18 (A2MI) and the GTC/ATC (VaIIO00IIe) in exon 24 (A2M2), may have roles in the development of Alzheimer's disease (AD). Genotyping and linkage analysis of these markers in 426 Japanese sporadic AD patients, 85 autopsy-confirmed Caucasian AD cases, and, as controls, 382 Japanese and 65 Caucasians who were cognitively normal and 140 Japanese Parkinson's disease patients showed racial diversity in the frequencies and relationship of the two markers. Comparison of genotype and allele frequencies, stratification of the samples by the presence of the apolipoprotein E epsilon4 allele, and logistic regression analysis revealed no association of these markers with AD in either racial group.
Aged↗
Development and validation of a liquid chromatographic-tandem mass spectrometric method for the determination of pibutidine in human urine.
A liquid chromatographic-tandem mass spectrometric method for the rapid quantitative determination of pibutidine, an H2-receptor antagonist, in human urine has been developed and validated over the concentration range 0.1-25.6 microg ml(-1). Urine samples were prepared based on a simple dilution with 0.05% acetic acid, followed by reversed-phase liquid chromatographic separation. Pibutidine and its internal standard (2H10-pibutidine) were ionized using an electrospray ionization interface and detected by tandem mass spectrometry in the selected reaction-monitoring mode. Completed validation demonstrated the method to be robust, accurate, precise and specific for the direct quantification of pibutidine in human urine. This method has enabled investigation of the urinary excretion of pibutidine following oral administration of pibutidine hydrochloride to healthy subjects.
Adult↗
Effect of alpha(1)-acid glycoprotein on the pharmacokinetics of tamsulosin in rats treated with turpentine oil.
The pharmacokinetics of tamsulosin (TAM) was investigated using male Sprague-Dawley rats in which plasma alpha(1)-acid glycoprotein (alpha(1)-AGP) levels were elevated by the subcutaneous injection of 0.2 mL/kg of turpentine oil. alpha(1)-AGP levels increased about eight times after turpentine oil treatment, causing a threefold decrease in plasma unbound fraction (f(u)) of TAM. When 0.3 mg/kg of TAM was dosed intravenously, total and nonrenal clearances (CL(tot) and CL(nr)) in turpentine-treated rats were 47% and 44% lower than those in nontreated controls, respectively. The area under the concentration-time curve of plasma unbound TAM (AUC(inf,u)) was lower than that in the control. When 1 mg/kg of TAM was dosed orally, oral clearance (CL(oral)) in alpha1-AGP-induced rats was 65% lower than in the control. The AUC(inf,u) and unbound oral clearance (CL(oral,u)) were nearly equal in both groups. Moreover, a positive correlation was observed between fu and CL(oral) of TAM (r(2) = 0.603, P < 0.01), whereas no correlation was observed between f(u) and CL(oral,u). The absolute bioavailability (BA) increased from 19.2% to 46.9% by induction of alpha(1)-AGP. These results suggest that decreased f(u) caused by the elevation of plasma alpha(1)-AGP level affects the pharmacokinetics of TAM, but does not affect the CL(oral,u,) which represents the hepatic metabolism of TAM.
Animals↗
Determination of YM992, a novel selective serotonin reuptake inhibitor, in rat and dog plasma by high-performance liquid chromatography with fluorescence detection.
A high-performance liquid chromatographic method with fluorescence detection was developed for the determination of (S)-2-[[(7-fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride (YM992) in plasma. Plasma samples were extracted with n-hexane under alkali condition. After the organic solvent was evaporated to dryness, the residue was treated with 4-fluoro-7-nitrobezofurazan (NBD-F) in borate buffer (pH 7.5) at room temperature for 20 min. The reaction was terminated with hydrochloric acid and the resultant solution was injected onto HPLC without further purification. No interfering peak was observed at the retention time of YM992 or the internal standard. The calibration curve was linear with the concentration of YM992 up to 200 ng/ml. The limit of quantitation was 1 ng/ml. The intra- and inter-day relative standard deviation was less than 5.6% and 4.1%, respectively, and the intra- and inter-day relative error ranged from -3.0% to 17.2% and 2.8% to 7.5%, respectively. Using the assay, the plasma concentration of YM992 could be determined up to 8 and 10 h after the oral administration of YM992 to rats and dogs, respectively.
4-Chloro-7-nitrobenzofurazan↗
Ability of osteoclast formation from peripheral monocytes using anti-fusion regulatory protein-1/CD98/4F2 monoclonal antibodies in patients with osteoporosis.
We investigated the difference in osteoclast formation between patients with osteoporosis and two healthy control groups by inducing it from peripheral blood monocytes with use of anti-fusion regulatory protein- monoclonal antibody. The group of patients with osteoporosis consisted of 35 women and excluded secondary osteoporosis, and the control groups consisted of 12 young healthy volunteers (control I) or 10 individuals age-matched to the patients with osteoporosis (control II). Osteoclast formation declined with age between the two control groups, but this decline was not significant. Fusion rate and the mean number of nuclei in osteoclasts were significantly less in the patients with osteoporosis than in the young or age-matched controls. It was clearly demonstrated that the ability of monocytes to fuse declines significantly in patients with osteoporosis.
Adult↗
Glucose hypometabolism and neuropathological correlates in brains of dementia with Lewy bodies.
Cerebral glucose metabolism using positron emission tomography (PET) with (18)F-fluorodeoxyglucose was examined in 11 patients with probable Alzheimer's disease (AD), 6 patients with probable, and 1 patient with autopsy-confirmed dementia with Lewy bodies (DLB) as well as in 10 age-matched normal control subjects. Among widespread cortical regions showing glucose hypometabolism in the DLB group, the metabolic reduction was most pronounced in the visual association cortex compared to that in the AD group. Using a metabolic ratio of 0.92 in the visual association cortex as a cutoff (mean-2 SD of normal control subjects), DLB could be distinguished from AD with a sensitivity of 86% and a specificity of 91%. In contrast, apolipoprotein E4 allele frequency and cerebrospinal fluid tau levels did not differ significantly between the two groups. In order to further dissect out neuropathological correlates of the dysfunctional occipital lobe, postmortem brains from 19 patients with AD and 17 with DLB as well as 11 brains from normal controls were examined. A distinct and extensive spongiform change with coexisting gliosis was variably noted throughout cerebral white matter with relative sparing of gray matter in DLB. Notably, the white matter spongiform change and gliosis was most prominently and consistently found in the occipital region of DLB, and the severity of the spongiform change in each brain region generally paralleled to the regional difference in reduced glucose metabolism between the living AD and DLB patients. These findings suggest that (1) among several potential antemortem biomarkers in the diagnosis of DLB, measures of the glucose metabolism in the occipital cortex may be an informative diagnostic aid to distinguish DLB from AD; and (2) a pathological process that generates widespread spongiform change and gliosis in long projection fibers may contribute, at least in part, to the characteristic imaging features of DLB.
Aged↗
Lack of differences in diclofenac (a substrate for CYP2C9) pharmacokinetics in healthy volunteers with respect to the single CYP2C9*3 allele.
OBJECTIVES: Evidence exists to suggest that diclofenac is metabolised by CYP2C9. The present study was undertaken in order to evaluate the effect of the single CYP2C9*3 variant on drug metabolism using diclofenac as a probe drug. METHODS: A single dose of diclofenac was administered orally to 12 healthy subjects in whom the genotype of CYP2C9 had been determined previously. The disposition kinetics of diclofenac were compared between homozygotes for the wild type (CYP2C9*1/*1, n = 6) and heterozygotes for the Leu359 variant (CYP2C9*1/*3, n = 6). RESULTS: For diclofenac, the following kinetic parameters were observed in the CYP2C9*1/*1 and CYP2C9*1/*3 subjects, respectively (mean +/- SD): apparent oral clearance (ml/kg/h) 355.8 +/- 56.9 and 484.4 +/- 155.3; area under plasma concentration time curve (microg h/ml) 2.7 +/- 0.7 and 1.9 +/- 0.6. The formation clearance of 4'-hydroxydiclofenac (ml/kg/h) was 63.6 +/- 19.1 in the CYP2C9*1/*1 subjects compared with 75.9 +/- 27.6 in the CYP2C9*1/*3 subjects. There were no significant differences in any of the kinetic parameters for either diclofenac disposition or formation clearance of 4'-hydroxydiclofenac between the two genotype groups. CONCLUSION: Since the disposition kinetics of diclofenac does not change in subjects with the single CYP2C9*3 mutant allele, it is suggested that the effects of CYP2C9 polymorphisms on the drug metabolism tend to be substrate specific.
Adult↗
No evidence of association between apolipoprotein E gene regulatory region polymorphism and Alzheimer's disease in Japanese.
The reported association between -491 A/T polymorphism in the regulatory region of the apolipoprotein E gene (APOE) and increased risk for Alzheimer's disease (AD) is controversial: Studies of different racial and ethnic populations have found both positive and negative associations. Examination of -491 A/T polymorphism in 216 patients with sporadic AD and 157 age- and gender-matched controls from the Japanese population revealed that, in contrast to findings for Caucasian populations, the -491 T allele, but not the A allele, was significantly more prevalent in patients with AD than in controls. This difference disappeared when the subjects were stratified by the gene dose of the APOE epsilon4 allele. Moreover, logistic regression analysis, controlling for age, sex, and the presence of the APOE epsilon4 allele, showed no association between the -491 polymorphism and AD. These results suggest that -491 polymorphism does not independently confer susceptibility to AD, but that this polymorphism is in partial linkage disequilibrium with the APOE epsilon2/3/4 polymorphism.
Aged↗