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Biomedical subjects

M Mimura

Publications and source records attributed to M Mimura.

At least 73 records · Page 4Linked to original sources
PubMed1994

Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians.

Interindividual variations in the level and activity of cytochrome P-450 enzymes were investigated in the liver microsomes of 30 Japanese and 30 Caucasian patients. The P-450 enzymes used in this study included P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A, and the monooxygenase activities determined were 13 typical P-450 substrates and 9 procarcinogens. Although the total P-450 content was higher in Caucasian (mean, 0.43 nmol/mg of protein) than in Japanese populations (mean, 0.26 nmol/mg of protein), the relative levels (percent of total P-450) of individual forms of P-450 determined immunochemically were not very different except that P-450 2A6 and 2B6 levels were higher in the Caucasians. About 70% of liver P-450 could be accounted for by P-450 1A2, 2A6, 2B6, 2C, 2D6, 2E1 and 3A proteins, and P-450 3A (about 30% of total P-450) and 2C (about 20%) enzymes were found to be the major forms. Considerable levels of P-450 1A2 (about 13%) and 2E1 (about 7%) could be determined, whereas the P-450 2A6 (about 4%), 2D6 (about 2%) and 2B6 (< 1%) were the minor P-450 forms. Differences in some of the P-450 1A2-, 2A6-, 2D6-, 2E1- and 3A4-dependent activities were observed in Japanese and Caucasian populations. No clear sex-related differences in individual P-450 contents and drug- and carcinogen-metabolizing activities were detected in 60 human samples, except that P-450 1A2-dependent activities were found to be higher in mean than in women in the Caucasian population only. A single neonate sample tended to be lower in P-450 1A2-, 2A6- and 2E1-dependent activities. In contrast to rat counterparts, we could not detect apparent developmental changes in P-450 content and activity in humans between 12 and 73 years old. Thus, the results presented in this study provide useful information for the study of drug biotransformation in humans and for the basis of drug toxicities, carcinogenesis and teratogenesis.

Adolescent↗
PubMed1993

Roles of different forms of cytochrome P450 in the activation of the promutagen 6-aminochrysene to genotoxic metabolites in human liver microsomes.

We reported previously that the potent mutagen 6-aminochrysene is catalyzed principally by rat liver microsomal P4501A and P4502B enzymes to reactive metabolites that induce umu gene expression in O-acetyltransferase-over-expressing strain Salmonella typhimurium NM2009; the proposal was made that there are different mechanisms in the formation of reactive N-hydroxylated and diolepoxide metabolites by P450 enzymes (Yamazaki, H. and Shimada, T., Biochem. Pharmacol., 44, 913-920, 1992). Here we further examined the roles of human liver P450 enzymes and the mechanism of activation of 6-aminochrysene by rat and human P450 enzymes in the Salmonella tester strains. Liver microsomes from 18 different human samples catalyzed activation of 6-aminochrysene more efficiently in S. typhimurium NM2009 than in the original strain of S. typhimurium TA1535/pSK1002. The rates of 6-aminochrysene activation in 18 human liver samples showed good correlation to the contents of P4502B6 as well as contents of P4503A4 and the respective mono-oxygenase activities catalyzed by P4503A4. Among purified P450 enzymes examined, P4501A2 as well as P4503A4 were highly active in transforming 6-amino-chrysene to reactive metabolites, suggesting the involvement of different human P450 enzymes in the reaction. Four human samples that contained relatively high levels of particular P450 enzymes in their microsomes were selected and used for further characterization. Liver microsomes from human samples HL-13 and HL-4 that contained the highest levels of P4502B6 and P4503A4 respectively, were sensitive to the respective antibodies raised against monkey P4502B and human P4503A4; the activity in sample HL-16 having the highest level of P4501A2 was inhibited by anti-P4501A2 IgG. alpha-Naphthoflavone enhanced the activation of 6-aminochrysene very significantly in human liver microsomes enriched in P4503A4 and P4502B6 enzymes. Pentachlorophenol, an inhibitor of acetyltransferase activity, suppressed the activation of 6-aminochrysene in liver microsomes from phenobarbital-treated rats and from human samples HL-4, HL-13 and HL-18 but not HL-16. In contrast, 1,1,1-trichloropropane-2,3-oxide, an inhibitor of epoxide hydrolase activity, enhanced the activation of 6-aminochrysene catalyzed by liver microsomes from beta-naphthoflavone-treated rats and from human samples HL-16 but not HL-4, HL-13 and HL-18. Inclusion of purified rat epoxide hydrolase to the reconstituted system containing rat and human P4501A enzymes caused a decrease in the rates of 6-aminochrysene activation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Synthesis and evaluation of (piperidinomethylene)bis(phosphonic acid) derivatives as anti-osteoporosis agents.

Some (piperidinomethylene)bis(phosphonic acid) derivatives were prepared and their activity to inhibit a rise in serum calcium induced by parathyroid hormone in thyroparathyroidectomised rats was evaluated. Several (4-alkylidene-, 4,4-dialkyl-, or 4-alkyl-4-halopiperidinomethylene)bis(phosphonic acid) derivatives showed considerable inhibitory activity. But compounds having aromatic and polar substituents such as azido, hydroxy, amino and amido on the piperidine ring were generally inactive. In this study, two 4-alkylidene compounds (8a and 8b) and a 4,4-cyclic dialkyl compound (61) showed potent activity when administered either intravenously or perorally.

Animals↗
PubMed1993

Exacerbation of ulcerative colitis during alpha-interferon therapy for chronic hepatitis C.

We report a 34-year-old man with chronic hepatitis C who showed exacerbation of ulcerative colitis during alpha-interferon (IFN alpha) therapy. Discontinuance of the IFN alpha therapy improved his symptoms, suggesting that IFN alpha administration might worsen ulcerative colitis. The administration of sulfasalazine allowed the patient to receive IFN alpha again without flare-up of ulcerative colitis. This case suggests the possible efficacy of sulfasalazine therapy in patients with ulcerative colitis complicated by some other diseases requiring IFN alpha administration.

Adult↗
PubMed1992

Rat pulmonary microsomal cytochrome P-450 enzymes involved in the activation of procarcinogens.

Rat lung microsomal cytochrome P-450 (P-450) enzymes have been characterized with regard to their catalytic specificities towards activation of several procarcinogens to genotoxic metabolites in Salmonella typhimurium TA1535/pSK1002. We first examined the roles of rat liver microsomal P-450 enzymes in the activation of benzo[a]pyrene and its 7,8-diol enantiomers to genotoxic products, and found that P-450 1A1 is a major catalyst for the activation of these potential procarcinogens in rat livers. Using lung microsomes isolated from rats treated with various P-450 inducers we obtained evidence that at least three P-450 enzymes are involved in the activation of several procarcinogens. Immunoinhibition studies support the view that benzo[a]pyrene and its 7,8-diol derivatives, other dihydrodiol derivatives of polycyclic aromatic hydrocarbons, and 3-amino-1-methyl-5H-pyrido[4,3-b]indole are activated to genotoxins mainly by rat P-450 1A1, which is inducible in rat lungs by 5,6-benzoflavone and the polychlorinated biphenyl mixture Aroclor 1254. Activation of 2-amino-3,5-dimethylimidazo[4,5-f]quinoline and 2-amino-3-methylimidazo[4,5-f]quinoline may be catalyzed by another P-450 enzyme because the activities were not induced by treatment with 5,6-benzoflavone or Aroclor 1254. The observation that both activities were inhibited by antibodies raised against P-450 1A2 and by 7,8-benzoflavone suggests a role for an enzyme of P-450 1A family, probably P-450 1A2, in rat lung microsomes. The activation of aflatoxin B1 and sterigmatocystin appears to be catalyzed by other P-450 enzyme(s) rather than the P-450 1A family as judged by the different responses of activities to the P-450 inducers and the specific antibodies in rat lung microsomes. Interestingly, lung microsomal activation of several procarcinogens was found to be suppressed in rats treated with isosafrole and pregnenolone 16 alpha-carbonitrile. Thus, the results support the roles of different P-450 enzymes in the activation of procarcinogens in rat lung microsomes.

Aflatoxins↗
PubMed1992

Reduction of erythrocyte (Na(+)-K+) ATPase activities in non-insulin-dependent diabetic patients with hyperkalemia.

To elucidate the mechanism of hyperkalemia in diabetic patients without renal failure, we investigated (Na(+)-K+) adenosine triphosphatase (ATPase) activity in erythrocyte membrane, erythrocyte Na+ and K+ content, and plasma endogenous digitalis-like substance in control subjects (n = 16) and non-insulin-dependent diabetes mellitus (NIDDM) patients (n = 62). NIDDM patients were divided into normokalemic patients (NKDM, n = 48) and hyperkalemic patients (HKDM, n = 14). There was no difference in plasma glucose or hemoglobin A1c (HbA1c) levels, plasma renin activity (PRA), and plasma aldosterone concentrations (PAC) between NKDM and HKDM patients. (Na(+)-K+)ATPase activities in NIDDM patients were significantly reduced compared with those in control subjects (0.336 +/- 0.016 mumol-inorganic phosphate [Pi]/mg protein/h, mean +/- SEM, P less than .05), and (Na(+)-K+)ATPase activities in HKDM patients (0.243 +/- 0.015 mumol Pi/mg protein/h) were significantly reduced compared with those in NKDM patients (0.295 +/- 0.008 mumol Pi/mg protein/h, P less than .01). Plasma K+ content had a significant negative correlation with (Na(+)-K+)ATPase activity in diabetic patients (r = -.365, P less than .01). Erythrocyte Na+ content had a significant negative correlation with (Na(+)-K+)ATPase activity in control subjects (r = -.619, P less than .05). There was no difference in plasma endogenous digitalis-like substance among the three groups. (Na(+)-K+)ATPase activity was not significantly correlated with plasma endogenous digitalis-like substance in control subjects and diabetic patients. These findings suggest that the reduction of (Na(+)-K+)ATPase activity, which was not related to plasma digitalis-like substance, may be partly responsible for hyperkalemia in diabetic patients.

Adult↗
PubMed1992

Central cholinergic action produces antagonism to ketamine anesthesia.

Ketamine sometimes produces posthypnotic emergency reactions, such as prolonged hallucination or delirium. In a previous paper, we showed that physostigmine, an anticholinesterase agent, counteracts the manifestation of effects of ketamine at some doses. In the present study, we investigated the mechanism of the antagonistic effect of physostigmine on ketamine anesthesia. At first, rats were given ketamine 75 mg/kg. Immediately after the loss of righting reflex, the four groups of rats were given one of the three central cholinergic agents, physostigmine 0.1 mg/kg, oxotremorine 0.05 mg/kg, 4-aminopyridine 3 mg/kg, or saline as the control. The sleeping times were 10.7 +/- 1.0, 12.3 +/- 0.9, 11.4 +/- 1.3 and 21.2 +/- 0.7 min, respectively. The three cholinergic agents antagonized ketamine anesthesia. In the other groups of rats, the central anticholinergic agent, l-hyoscyamine, 0.5 mg/kg, was given subcutaneously for premedication before the above-mentioned procedure. The sleeping times were 16.3 +/- 1.2 min in the physostigmine group, 18.7 +/- 1.0 min in the oxotremorine group and 18.6 +/- 0.8 min in the 4-aminopyridine group. The sleeping time was significantly longer in the premedicated group than in the non-premedicated group, in the case of the three central cholinergic agents. The sleeping time in the saline group, 20.0 +/- 0.4 min, was not significantly different from that of the control in the non-premedicated case. It is, therefore, considered that the central cholinergic action produces antagonism to ketamine anesthesia.

4-Aminopyridine↗
PubMed1992

Deficits of problem-solving ability in patients with focal brain damage: neuropsychological investigation of prediction and hypothesis behavior.

Deficits of problem-solving ability in focal brain-damaged patients, with special reference to frontal lobe dysfunction, were investigated by two neuropsychological tests: Temporal rule induction test and Hypothesis-testing measure. Subjects consisted of 84 chronic brain-damaged patients (31 with anterior cerebral lesions and 53 with posterior lesions). The study's aim was to investigate the effects of frontal lobe damage on two aspects of inductive reasoning, prediction and hypothesis behavior. When prediction was examined by Temporal rule induction test, patients with anterior lesions showed deficits in predicting a rule, even in the memory-aid condition in which memory factors were excluded. The poor results on Temporal rule induction test in frontal patients did not appear to be related to deficits in temporal integration, which is generally interpreted as frontal dysfunction. Rule induction may be impaired by frontal damage whenever complicated information-processing is required, even when temporal succession is not involved. Second, two stages of hypothesis behavior, hypothesis-formation and hypothesis-testing, were evaluated. Patients with anterior lesions showed impairment in hypothesis-formation. Their decreased fluency in hypothesis production affected the hypothesis-testing process. However, frontal patients committed fewer errors, most of which were perseverative (lose-stay errors) on hypothesis-testing. Patients with posterior lesions revealed other characteristic errors, such as inconsistent responses and divergent-type errors (improper lose-shift errors). The hemispheric site of the lesion affected only the ability to maintain a hypothesis (win-shift errors). The results illustrated the differences in problem-solving deficits in these two groups of patients. Disturbed prediction of future events, decreased hypothesis fluency, and abnormal lose-stay behavior in patients with frontal lobe damage may be crucial factors in coping with daily problem-solving situations.

Brain Damage, Chronic↗
PubMed1991

Defects in insulin binding and receptor kinase in cells from a woman with type A insulin resistance and from her family.

Defects in insulin receptor function lead to impairment of the insulin response. We treated a patient with the typical phenotype of type A syndrome of insulin resistance whose insulin receptor seemed to lack the transmembrane region and cytoplasmic domain. Hyperinsulinaemia and resistance to exogenous insulin were evident, and insulin binding to cells and uptake of 2-deoxyglucose into fibroblasts were greatly decreased. Molecular weight of the alpha-subunit of the insulin receptor was normal, but autophosphorylation and kinase activity were impaired. In the pedigree analysis, defects in insulin binding were also observed in the mother, maternal grandfather and two maternal aunts, corresponding with the abnormality of the insulin receptor gene and mild insulin resistance. In the mother, much the same kinase defects as were seen in the patient became evident. However, no relatives had clinical symptoms similar to those seen in the patient. In the father there was a mild insulin resistance in the glucose clamp study and a borderline impaired glucose tolerance. Although insulin binding to cells was normal in the father, both autophosphorylation and kinase activity were reduced. Our findings suggest that insulin resistance in the patient may be caused by the defects in insulin receptor kinase activity as well as by a reduction in insulin binding activity.

Adolescent↗
PubMed1990

Antagonistic effect of physostigmine on ketamine-induced anesthesia.

Effects of physostigmine on ketamine-induced anesthesia and analgesia were studied in male Sprague-Dawley rats using behavioral tests. Rats were divided into six groups. Immediately after loss of the righting reflex following an intraperitoneal injection of ketamine 75 mg/kg, each group of rats was given an intraperitoneal injection of either physostigmine 0.05, 0.1, 0.2, 0.4, 0.6 mg/kg or saline as the control, respectively. Physostigmine 0.1 mg/kg caused the greatest antagonistic effect on ketamine anesthesia as indicated by sleeping time, duration of ataxia and motor coordination. The antagonistic effects of physostigmine were reduced by a dose of physostigmine of greater than 0.1 mg/kg. However, at no dose did physostigmine antagonize ketamine analgesia as indicated by the tail-flick latency. Physostigmine (0.4 and 0.6 mg/kg) itself had analgesic and motor-suppressive actions. It can therefore be presumed that there is a limited threshold of the dose of physostigmine which develops an antagonistic effect on ketamine anesthesia due to the motor-suppressive action. It is also confirmed that physostigmine itself produces analgesia, and does not antagonize ketamine-induced analgesia.

Anesthesia↗
PubMed1990

Long-term results of anterior interbody fusion for treatment of degenerative spondylolisthesis.

Thirty-nine patients, 34 women and five men, underwent anterior decompression and interbody fusion for degenerative spondylolisthesis between February 1958 and August 1988. Their average age at surgery was 51 years (range, 34-74 years), and their average follow-up period was 12 years 7 months (range, 6 months to 30 years). Clinical evaluation was done by the score rating system of the Japanese Orthopaedic Association (JOA Score). Patients with JOA scores of 25 points or more were rated as "satisfactory." Survivorship was analyzed by the method of Kaplan and Meier to determine the cumulative percentage of patients with satisfactory results. The following results were obtained: Seventy-six percent of the patients had satisfactory results for 10 years after the anterior interbody fusion, 60% for 20 years, and 52% for 30 years. Irrespective of their age at surgery, the patients generally maintained satisfactory results up to 65 years of age.

Female↗
PubMed1990

[Rotational instability of the lumbar spine--a three-dimensional motion study using bi-plane X-ray analysis system].

The purpose of this study is to investigate the rotational instability of the lumbar spine using bi-plane X-ray analysis system and to clarify mechanical etiology of the lumbar instability. The following results were obtained. (1) The range of rotational motion was about 2 to 3 degrees at each motion segment in the normal lumbar spine. The rotational motion was significantly large in spondylolysis, spondylolisthesis, and degenerative spondylolisthesis. (2) The rotational instability and the flexion-extension instability correlated to each other in spondylolysis and spondylolisthesis. However, in degenerative spondylolisthesis, the rotational instability and the antero-posterior instability were correlated to each other. (3) Instantaneous axis of rotation (IAR) was located at the posterior part of the intervertebral disc in the normal L4 vertebra, and more posteriorly in the L5 vertebra, while the IAR was located anteriorly in spondylolysis, and posteriorly in degenerative spondylolisthesis. (4) When the trunk was twisted, the lumbar lordotic angle was generally decreased, and the lumbar spine showed scoliotic curvature convex to the twisted direction. The apex was located at the L4/5 intervertebral level. Highly significant increases in flexion motion associated with rotation were observed at the pathological levels of spondylolysis and degenerative spondylolisthesis.

Adult↗
PubMed1989

Three-dimensional motion analysis of the cervical spine with special reference to the axial rotation.

The purpose of this study is to obtain basic data on the rotational motion of the cervical spine. Twenty normal men aged 25 to 31 years were investigated. Biplanar roentgenograms of the neck with the head held in neutral and maximally rotated positions were taken in a reference frame. Three sets of x-ray films were measured using a three-dimensional analysis system composed of a digitizer and a personal computer. Total axial rotation was 105 degrees on an average between the occiput and the C7 vertebra. Seventy percent of the total axial rotation occurred between the occiput and the C2 vertebra. Each motion segment between the C2 and C7 vertebrae showed from 4 degrees to 8 degrees rotation on an average. When the head was rotated, lateral bending occurred by coupling in the same direction as rotation at each segment below the C3-C4 level, and in the opposite direction above the C2-C3 level. At the same time, flexion took place by coupling at each segment below the C5-C6 level, and extension above the C4-C5 level.

Adult↗
PubMed1989

[Penicillin insensitive and resistant Streptococcus pneumoniae infection in children].

Five cases of penicillin insensitive or resistant pneumococcal infection in children were experienced during the period of 2 years since March, 1986. One isolate from middle ear showed the MIC of 4 micrograms/ml against penicillin-G. One isolate of insensitive pneumococcus was isolated from CSF specimen. Between 1976 and 1987, 59 isolates from 88 stocked pneumococcal clinical isolates were alive. These 59 strains were screened by oxacillin disc for insensitive and resistant pneumococcus. Five strains which were insensitive or resistant strains had inhibitory zone under 20 mm. The prevalence rate of insensitive or resistant pneumococcus since 1986 was 18%.

Humans↗