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Biomedical subjects

S Higuchi

Publications and source records attributed to S Higuchi.

At least 271 records · Page 15Linked to original sources
PubMed1996

Association of aldehyde dehydrogenase with inheritance of NIDDM.

To investigate the influence of the mitochondrial aldehyde dehydrogenase 2 (ALDH2) genotype on the clinical features of diabetes, 212 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) (154 males and 58 females aged 17-83 years; mean age 58.2 years) were investigated. Genotyping of ALDH2 was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The pattern of inheritance of diabetes and various clinical parameters was compared between active and inactive ALDH2 groups. Of the 212 subjects, 120 had active ALDH2 and 92 had inactive ALDH2. The percentage of patients with a diabetic mother was higher in the inactive ALDH2 group (32.6%) than in the active ALDH2 group (19.2%) (p < 0.05). The prevalence of proliferative retinopathy was lower in the inactive ALDH2 group than in the active ALDH2 group (p < 0.05). However, other clinical parameters showed no difference. We conclude that maternal inheritance of diabetes was common in the inactive ALDH2 group. The finding is suggestive of a relationship between alcohol intolerance and inheritance of diabetes. We speculate that the interaction between mitochondrial DNA and ALDH2 inactivity causes an increase of mitochondrial DNA mutations or deletions, thereby inducing the maternal inheritance of diabetes. The relationship of the ALDH2 genotype with proliferative retinopathy is interesting, because it resembles that of chlorpropamide alcohol flushing with severe diabetic retinopathy. The interaction of aldehyde dehydrogenase isoenzymes might have an aetiological role, since aldehyde dehydrogenase 1 plays an important part in oxidation of retinal to retinoic acid. However, the number of affected patients with proliferative retinopathy was small, hence, our result should be considered as a preliminary finding.

Adolescent↗
PubMed1996

Alpha 1-antichymotrypsin gene polymorphism and risk for Alzheimer's disease.

alpha 1-Antichymotrypsin (ACT), a component of the senile plaque of the Alzheimer's disease (AD) brain, has a possible role as a molecular chaperone in developing AD pathology. This study was a search for the possible association of the two structural polymorphisms of ACT, Ala15-->Thr and Met389-->Val in the Japanese population. In 101 AD patients, genotype and allele frequencies of the two polymorphisms did not differ from those of 104 age-matched healthy controls. However, in those subjects in which the apolipoprotein epsilon 4 allele was absent, the frequency of the Ala15 homozygote was significantly higher in the AD patients than in controls. This suggests that the Ala15 homozygote state may be a susceptibility marker for AD, interacting with apolipoprotein E genotype.

Aged↗
PubMed1996

Polymorphisms of ethanol-oxidizing enzymes in alcoholics with inactive ALDH2.

Inactive aldehyde dehydrogenase-2 (ALDH2) is a well-known biological deterrent of heavy drinking among Asians, although some individuals who have inactive ALDH2 do become alcoholics. Unknown biological mechanisms facilitating the development of the disease may operate in such a way that these individuals overcome adverse reactions, or they may lower the intensity of the reactions. To examine our hypothesis that ethanol-oxidizing isoenzymes have lower catalytic properties in some persons, we investigated polymorphisms of ethanol-oxidizing enzymes that may alter their catalytic activities, viz., alcohol dehydrogenase-2 (ADH2) and -3 (ADH3), and cytochrome P450 2E1 (CYTP2E1), among 80 Japanese alcoholics with inactive ALDH2, 575 alcoholics with active ALDH2, and 461 controls. Although higher ADH2*1 and ADH3*2 allele frequencies were observed in alcoholics than in controls, there was no significant difference in ADH2 and ADH3 genotypes between alcoholics with inactive ALDH2 and alcoholics with active ALDH2. The genotype distributions of CYTP2E1 did not differ among the three groups, indicating no allelic association of the c1/c2 polymorphism of CYTP2E1 with alcoholism. These results suggest that genetic variations in ethanol-oxidizing activities are involved in the development of the disease, but that these variations are not specific in alcoholics with inactive ALDH2, a group at genetically low risk for alcoholism.

Adult↗
PubMed1996

Purification of bovine beta 2-microglobulin from colostrum and its complete amino acid sequence.

Bovine beta 2-microglobulin (beta 2-m) was purified from colostrum milk in two chromatographic steps: anion-exchange chromatography, and gel filtration. The amino acid sequence was determined to confirm that the purified protein was beta 2-m. A molecular weight of 11.8 kDa beta 2-m was estimated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Bovine beta 2-m consists of 98 amino acid residues and contains one disulfide linkage connecting residues 25 and 79. The amino acid sequence determined by this study is different from a previously published sequence at three sites, but agrees with the amino acid sequence from cDNA. Thus, we can conclude that the amino acid sequence determined in this study is correct.

Amino Acid Sequence↗
PubMed1996

Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles, C gamma P2C19m1 in exon 5 and C gamma P2C19m2 in exon 4, in Japanese subjects.

The pharmacokinetic profile of omeprazole was examined in 27 healthy Japanese volunteers, and the results were analyzed in relation to genotype for the two mutations, CgammaP2C19m1 in exon 5 and CgammaP2C19m2 in exon 4, associated with the poor metabolizer phenotype. Of the 27 individuals analyzed, 10 were homozygous for the wild-type (wt) allele in both exon 5 and exon 4 (wt/wt; 37.0%, pattern GI), five were heterozygous for the CgammaP2C19m1 (wt/m1; 18.5%, G2), five were heterozygous for the CgammaP2C19m2 (wt/m2; 18.5%, G3), two were heterozygous for the two defects (m1/m2; 7.4%, G4), and five were homozygous for the CgammaP2C19m1 (m1/m1; 18.5%, G5). The allele frequencies of the m1 and m2 mutation were 0.31 and 0.13, respectively. A correlation between the rate of metabolism of omeprazole and genotype was observed. The mean clearance values of omeprazole in patterns G1, G2, G3, G4, and G5 were 1369.0, 332.7, 359.0, 70.8, and 89.5 ml/hr/kg, respectively. The relative area under the serum concentration-time curve (AUC) ratio of omeprazole to 5-hydroxyomeprazole in patterns G1, G2, G3, G4, and G5 was 1:2.8:3.4:16:17.2. A similar relation was observed in the omeprazole/5-hydroxyomeprazole serum concentration ratio, determined 3 hours after drug intake (1:3:4:18.8:20.3). There were significant (p < 0.05 to 0.01) differences in the disposition kinetics of omeprazole between the subjects with patterns G1, G2, and G3 and the subjects with patterns G4 and G5. The results indicate that the 5-hydroxylation pathway of omeprazole is clearly impaired in subjects with m1/m2 and m1/m1.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1996

The apolipoprotein E gene in Binswanger's disease and vascular dementia.

We investigated the polymorphism of the apolipoprotein E (ApoE) gene using a PCR-RFLP method in patients with Binswanger's disease (BD), non-BD vascular dementia, or Alzheimer's disease (AD). The frequency of the epsilon 4 allele of the ApoE (ApoE4) in BD patients and non-BD vascular dementia patients did not differ from that observed in the nondemented elderly controls, but it was significantly lower than the frequency in AD patients. These results and other recent observations suggest that one or more factors other than the ApoE gene contribute to the pathogenesis of dementia in BD and non-BD vascular dementia.

Aged↗
PubMed1996

Alcohol and aldehyde dehydrogenase genotypes and drinking behavior in Japanese.

The effects of the genotype of alcohol dehydrogenase-2 (ADH2) and mitochondrial aldehyde dehydrogenase (ALDH2) on drinking behavior were investigated in a population of 451 Japanese. Although the ALDH2*2 allele had a significant inhibitory effect on alcohol consumption, hence on drinking problems, the apparent association was not confirmed between ADH2 genotype and overall drinking patterns for either males or females. However, the frequency of the ADH2*2 allele was significantly lower in male Japanese classified as alcoholic on the basis of the Kurihama Alcoholism Screening Test than in nonalcoholic males. These results corroborate a previous study that revealed a significantly lower ADH2*2 allele frequency in hospitalized Japanese alcoholics than in the general population. Together, these studies suggest that the ALDH2*2 allele has an inhibitory effect on drinking behavior, irrespective of the level of alcohol consumption, whereas the effect of the ADH2 polymorphism only becomes apparent in individuals with higher alcohol consumption, such as alcoholics.

Adolescent↗
PubMed1996

Alcohol and substance use among Japanese high school students.

In the first large-scale survey on the use of alcohol and tobacco and the inhalation of paint thinner by Japanese high school students, a higher percentage of respondents reported past or regular use of these substances than in a 1978 survey. The survey was conducted in 44 high schools. The 14,438 respondents (ages 15-18 years) represented 9 of Japan's 47 geographically distinct urban and rural prefectures. Most (76%) reported that they had consumed alcohol at some time, and 50% reported drinking on a regular basis. Alcohol consumption, drinking partners, and motivation for drinking were compared by student gender, geographic region, and years of education. Fewer students reported smoking cigarettes: 32% had smoked at some time, and 14% smoked regularly. Inhalation of paint thinner was rare: 3% had purposely inhaled it, and 1% had abused it. A significant percentage of the alcohol drinkers also used tobacco and/or thinner, a tendency that was the same despite differences in gender, grade in high school, and urban or rural geographic region. A tendency toward polysubstance use was evident among these high school students.

Adolescent↗
PubMed1996

Effect of dose, sex and age on the drug disposition of incadronate, a new bisphosphonate, in rat bone.

We investigated the effects of dose, sex and age on the uptake and elimination of incadronate, a new biosphosphonate, in rat bone after intravenous administration. Following administration of 0.03-3 mg/kg to young male rats (age 7 weeks),intact drug concentration in humerus at 24 hr after administration (C24 hr) increased in a dose-dependent manner, indicating the linear uptake of the drug into bone. The estimated bone uptake clearance of 0.13 ml/min./g bone is comparable to the estimated plasma flow rate in bone, suggesting that uptake into bone is plasma flow-limited. Concentration from 24 hr after administration had declined bi-exponentially. Although t1/2 beta (350-444 days) was little altered among doses, t1/2 alpha was prolonged with increasing dose from 13.4 to 16.2 days. This effect seemed to be due to inhibition of bone resorption at higher doses resulting in the suppression of drug release from bone. No sex difference was seen on C24 hr in young rats, while the value in senescent (age 12 months) rats was 24% greater in females than in males. When comparing between ages it is seen that C24 hr values in senescent rats decreased to 50-66% of those in young rats. As for elimination from bone, t1/2 beta values in senescent rats were shortened to 76-79% of those in young rats. In contrast, little difference in t1/2 alpha was observed between ages or in either t1/2 alpha and t1/2 beta between sexes.

Aging↗
PubMed1996

Pharmacokinetic study of zonisamide in patients undergoing brain surgery.

To test whether the concentration of the anticonvulsant zonisamide in erythrocytes reflects the brain concentration and the clinical response of the drug, its pharmacokinetics were studied in nine patients undergoing surgery for brain tumour. Erythrocyte, total and free serum concentrations in samples drawn on the day of brain surgery were compared with levels on a day after the operation. In three patients zonisamide and its major metabolite, 2-sulphamoylacetylphenol, were also analysed in urine. The area under the curve of the free and the erythrocyte concentration did not differ between the two study phases whereas the area under the curve of the total serum concentration was significantly lower on the day of the operation, and this was associated with significant increases in total clearance (15.4 compared with 12.7 mL kg-1 h-1, P < 0.05, n = 9) and renal clearance (5.4 compared with 3.3 mL kg-1 h-1, P < 0.05, n = 3), and non-significant change in non-renal clearance (7.7 on the day of operation compared with 8.4 mL kg-1 h-1 on the post-operation day, n = 3). Zonisamide distribution was also altered by the operative procedure, as evidenced by a higher volume of distribution (1.48 compared with 0.87 L kg-1, P < 0.05, n = 9). The binding of zonisamide was characterized on both days. Zonisamide binding to erythrocytes seemed to occur by two processes: a saturable process and a non-saturable linear process. The maximum binding capacity to erythrocytes (31.6 vs 29.7 micrograms mL-1) did not differ on the two days; however, increases in the dissociation binding constant (+28%) and the proportionality constant (+24%) were observed on the day of the operation, suggesting that the zonisamide concentration in erythrocytes was greater on the day of the operation. Brain surgery appears to be one of the possible factors altering the rate of elimination of zonisamide and the uptake of the drug by erythrocytes.

Adult↗
PubMed1996

In-vitro metabolism of YM17E, an inhibitor of acyl coenzyme A:cholesterol acyltransferase, by liver microsomes in man.

Because YM17E (1,3-bis[[1-cycloheptyl-3-(p-dimethylaminophenyl) ureido]methyl]benzene dihydrochloride) inhibits acyl coenzyme A:cholesterol acyltransferase (ACAT) it has potential application in the treatment of hypercholesterolaemia. In man and animals YM17E is extensively metabolized, via N-demethylation, to five active metabolites (M1, M2-a, M2-b, M3 and M4). The main objectives of this study were to examine inhibition of YM17E metabolism by the products and identify the cytochrome P450 isoforms in liver microsomes which catalyse in-vitro YM17E metabolism in man. In microsomes in man N-demethylation of YM17E to M1 occurred enzymatically; for up to 45 s the rate was linearly proportional to the microsomal protein concentration. This reaction was inhibited by metabolites M2-a, M2-b, M3 and M4. Further, N-demethylation of [14C]-YM17E was also inhibited by its product, M1. These results showed that primary metabolism of YM17E was inhibited by its products, and supported the finding that the non-linear increase in plasma concentration of the parent drug and metabolites observed in an in-vivo study was due to inhibition by these products. Metabolic activity in microsomes from ten individual human livers demonstrated that YM17E N-demethylase activity correlated closely with testosterone 6 beta-hydroxylase activity. When cytochrome P450 isozyme-specific substrates and chemical inhibitors were used to inhibit YM17E N-demethylase activity, CYP3A-specific substrate and inhibitors such as nifedipine, ketoconazole and triacetyloleandomycin strongly inhibited this activity, whereas CYP1A-specific substrate or inhibitor, ethoxyresorufin and alpha-naphthoflavone, inhibited weakly. Other CYP inhibitors, in contrast, had few or no effects. An inhibition study using anti-rat CYP1A1, CYP2B1, CYP2C11, CYP2E1 and CYP3A2 antibodies demonstrated that only anti-rat CYP3A2 antibody inhibited YM17E metabolism, to 40% of control level, with no other antibodies showing an inhibitory effect. Of seven cDNA-expressed P450 isoforms in man (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 and CYP3A4), CYP3A4, CYP2D6 and CYP1A2 isozyme exhibited substantial catalytic activity of N-demethylation of YM17E. These results indicate the predominant role of CYP3A4 in liver metabolism of YM17E in man.

Chromatography, High Pressure Liquid↗
PubMed1996

Association between alcoholism and the dopamine D4 receptor gene.

A point mutation in the aldehyde dehydrogenase 2 gene (ALDH2(2) allele) is considered to be a genetic deterrent for alcoholism; however, 80 of 655 Japanese alcoholics had the mutant allele. Genotype factors that might increase susceptibility by overriding the deterrent showed a higher frequency of a five repeat allele of the dopamine D4 receptor 48 bp repeat polymorphism in alcoholics with ALDH2(2) than in 100 other alcoholics and 144 controls. Alcoholics with the five repeat allele also abused other drugs more often. These data suggest the involvement of the dopamine system in the development of alcoholism and other addictive behaviour.

Adult↗
PubMed1996

Pharmacokinetics of tamsulosin hydrochloride in patients with renal impairment: effects of alpha 1-acid glycoprotein.

The pharmacokinetics of tamsulosin hydrochloride in patients with renal impairment were compared with those in healthy volunteers, and the factors that influenced plasma levels of tamsulosin were elucidated. A single oral dose of 0.2 mg of tamsulosin was given and blood and urine samples were obtained for 36 hours after administration. Unbound plasma concentration of tamsulosin was measured by a combination of equilibrium dialysis and liquid chromatography tandem mass spectrometry methods to examine the effect of protein binding on the pharmacokinetics of tamsulosin. Mean values for maximum concentration (Cmax) and area under the concentration-time curve (AUC) of total drug (Cmax,t and AUC1) in patients with renal impairment were 73% and 211% greater, respectively, than those in healthy volunteers. Mean Cmax and AUC of unbound drug (Cmax,u and AUCu), however, were almost the same in the two groups. A high correlation was found between alpha 1-acid glycoprotein (alpha 1-AGP) concentration and AUCt, but no correlation was found between alpha 1-AGP concentration and AUCu,0-36) or between creatinine clearance (ClCR) and AUCu,0-36). These results show that in patients with renal impairment, the pharmacokinetics of tamsulosin are affected by the change in protein binding that is associated with alteration of plasma alpha 1-AGP concentration, but are not largely affected by the decrease in the renal excretion. Although total tamsulosin levels increased as plasma protein binding increased, unbound tamsulosin levels (which are directly associated with the pharmacologic effects) remained unchanged in these patients.

Adrenergic alpha-Antagonists↗
PubMed1996

Differential subcellular localization of neural isoforms of the catalytic subunit of calmodulin-dependent protein phosphatase (calcineurin) in central nervous system neurons: immunohistochemistry on formalin-fixed paraffin sections employing antigen retrieval by microwave irradiation.

We examined the immunohistochemical distribution of the two mammalian isoforms of calcineurin catalyic subunits, A alpha and A beta, in central nervous system (CNS) tissues of cows, rats, and humans. Cryostat sections and paraffin sections of parformaldehyde-fixed tissues were stained with antipeptide antibodies for each isoform. The same localization pattern was observed in both cryostat and paraffin sections. In the latter, the intensity of the staining was dramatically enhanced by microwave irradiation. Calcineurin isoforms were localized in a variety of nerve cells but not in neuroglial cells. Their differential expression as the A alpha isoform in the nucleus and the A beta isoform in the cytoplasm was present in a variety of CNS nerve cells, most distinctively in Purkinje cells of the cerebellum and pyramidal cells of the cerebrum, irrespective of species. These results suggest that each isform has distinct intracellular sites of action in CNS neurons and that the phenomenon has been conserved during mammalian evolution.

Amino Acid Sequence↗
PubMed1996

Effect of cilostazol, a novel anti-platelet drug, on restenosis after percutaneous transluminal coronary angioplasty.

The possible preventive effect of cilostazol, a novel anti-platelet drug, on restenosis after successful percutaneous transluminal coronary angioplasty (PTCA) was examined. One hundred and two consecutive patients, who underwent successful PTCA, were followed for 3 to 6 months. To prevent restenosis, 46 patients (60 PTCA sites) were treated with cilostazol alone (200 mg/day) (cilostazol group) and the remaining 56 (61 PTCA sites) were treated with other anti-platelet drugs and/or warfarin potassium (control group). Restenosis was defined as a more than 50% loss of the initial gain of the coronary diameter achieved by PTCA. Cilostazol did not significantly reduce the patient or lesion restenosis rate; the patient restenosis rate was 32% in the control group and 22% in the cilostazol group (P = 0.24), and the lesion restenosis rate was 30% in the control group and 23% in the cilostazol group (P = 0.44). However, the lesion non-progression rate, which was defined as the incidence of lesions with either no change or regression of coronary stenosis at the PTCA site, was significantly greater with cilostazol (37%) than in the control group (16%) (p < 0.05). Although cilostazol failed to show a significant reduction in restenosis after PTCA, the present results suggest that a further trial with a larger number of patients is needed to confirm its usefulness.

Aged↗
PubMed1996

Granulocyte activation in restenosis after percutaneous transluminal coronary angioplasty.

To examine whether or not granulocyte activation is involved in restenosis after percutaneous transluminal coronary angioplasty (PTCA), we prospectively followed the time course of the plasma level of granulocyte elastase, which is an index of granulocyte activation, before and after successful angioplasty in 43 consecutive patients. Restenosis was defined as a more than 50% loss of the initial gain in the coronary diameter achieved by PTCA with more than a 50% resultant stenosis in the follow-up coronary arteriography performed 3 months after PTCA. There was no difference in the level of granulocyte elastase between the 2 groups with (n = 15) and without (n = 28) restenosis before, the day after and 1 month after PTCA. However, 3 months after PTCA, the level of granulocyte elastase was significantly higher in the group with restenosis than in that without restenosis (171 +/- 13 vs 147 +/- 6 mg/l, P < 0.05). The level of granulocyte elastase at 3 months after PTCA also correlated significantly with the percent luminal stenosis at the angioplasty site (P < 0.05). These results suggest that granulocyte activation may be involved in restenosis after PTCA.

Adult↗
PubMed1996

Mitochondrial aldehyde dehydrogenase in diabetes associated with mitochondrial tRNA(Leu(UUR)) mutation at position 3243.

OBJECTIVE: To ascertain why alcohol is prone to manifest unpleasant effects in diabetes associated with mitochondrial tRNA(Leu(UUR) mutation at position 3243 (DM-Mt3243), we investigated the genotype of aldehyde dehydrogenase (ALDH) 2 and alcohol dehydrogenase 2 (ADH2) in DM-Mt3243. RESEARCH DESIGN AND METHODS: Nineteen unrelated patients with DM-Mt3243 were included in the study (12 men and 7 women). They were recruited from approximately 700 diabetic patients at three different institutes, without prior information of alcohol habit. ALDH2, ADH2, and 3243 mutation were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) methods. There were 461 unrelated Japanese individuals and 170 non-3243 mutant NIDDM patients enrolled as control subjects. RESULTS: In the DM-Mt3243 group, 15 (79%) patients had inactive ALDH2 and 18 (95%) had atypical ADH2. The frequency of the inactive ALDH2 genotype was higher than that in the normal control subjects (P < 0.002) and that in the NIDDM control subjects (P < 0.003). However, the frequencies of ADH2 genotype in the DM-Mt3243 group, the normal control subjects, and the NIDDM control subjects were not different. CONCLUSIONS: Inactive ALDH2 genotype was frequently observed in DM-Mt3243. It suggests that DM-Mt3243 is associated with ALDH2 inactivity. We speculate the trait of acetaldehyde accumulation on ALDH2 inactivity may favor mitochondrial DNA abnormalities, thereby worsening ATP production and impairing insulin secretion. In addition, the interaction of ALDH1 and ALDH2 may alter the retinoid metabolism in the pancreas, thereby influencing insulin secretion and precipitating diabetes. Thus, this association of ALDH2 genotype with DM-Mt3243 provides insight into the etiology of diabetes in the mitochondrial diseases.

Adult↗