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Biomedical subjects

M Kitada

Publications and source records attributed to M Kitada.

At least 91 records · Page 5Linked to original sources
PubMed1995

[Malignant mediastinal lesions with invasion to the superior vena cava].

Four patients underwent resection of mediastinal malignant tumors with invasion to the superior vena cava. Two patients had invasive thymoma, one seminoma, and one metastatic mediastinal lymph nodes of unknown origin. Prior to resection of the tumor, an ePTFE graft was anastomosed between the innominate vein and the right atrium to maintain the venous drainage from the brain and the upper extremities. In two patients, the superior vena cava was reconstructed by patch angioplasty after the tumor with a part of the vena cava was safely resected. One patient died of acute respiratory failure, but the other three are alive and well without any evidence of graft obstruction. This safe and useful method in order to prevent cerebral congestion during and after resection of the tumor.

Adult↗
PubMed1994

Possible occurrence of P450 related to P450 HFLb in extrahepatic tissues of human fetuses and its contribution to metabolic activation of promutagens.

P450 HFLb purified from human fetal livers has been shown to be constitutively expressed in fetal livers. In the present study, the occurrence of proteins immunochemically related to P450 HFLb in extrahepatic tissues of human fetuses and their contribution to mutagenic activation of promutagens were investigated. The mutagenic activation of aflatoxin B1 (AFB1), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and benzo[a]pyrene were observed in human fetal extrahepatic tissues, including adrenal glands, kidneys and lungs, at varying rates. Immunoblot analysis of homogenates of extrahepatic tissues with antibodies to P450 HFLb revealed the occurrence of proteins immunochemically related to P450 HFLb in adrenal glands, kidneys and lungs. Immuno-inhibition studies suggested that in fetal adrenal gland and kidney, the proteins cross-reactive with antibodies to P450 HFLb were capable of activating IQ and MeIQ to mutagens.

Adrenal Glands↗
PubMed1994

Chemiluminescence associated with doxorubicin-induced lipid peroxidation in rat heart mitochondria.

Chemiluminescence was observed in a rat heart mitochondrial suspension containing NADH, FeC1(3) and doxorubicin (Adriamycin) (DXR). There was good correlation between the total intensity of chemiluminescence and the total amount of thiobarbituric acid reactive substances (TBARS) produced during DXR redox cycling. Thus, the chemiluminescence was shown to be associated with lipid peroxidation. The chemiluminescence was quenched by superoxide dismutase (SOD), suggesting that superoxide anion radicals contributed to its production. Upon addition of 1,4-diazabicyclo[2,2,2]-octane (DABCO), a singlet oxygen emission enhancer, to the mitochondrial suspension emitting the chemiluminescence, the chemiluminescence intensity increased transiently, indicating the involvement of singlet oxygen. Furthermore, spectral analysis of the chemiluminescence showed it to be due to singlet oxygen and excited carbonyls.

Animals↗
PubMed1994

Characterization of monkey cytochrome P450, P450 CMLd, responsible for S-mephenytoin 4-hydroxylation in hepatic microsomes of cynomolgus monkeys.

We isolated a new form of cytochrome P450 (P450) which was able to catalyze S-mephenytoin 4'-hydroxylation from hepatic microsomes of cynomolgus monkeys. The final preparation (referred to as P450 CMLd) was apparently homogenous judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and the estimated minimum molecular weight of this protein was 53 kDa. The N-terminal amino acid sequence of P450 CMLd (identified 16 residues) was identical with that of protein encoded by P450 2C9 cDNA. P450 CMLd was cross-reactive with both antibodies raised against P450 2C11 and P450 2C9 which were purified from hepatic microsomes of male rats and humans, respectively. In hepatic microsomes of cynomolgus monkeys, both antibodies recognized two proteins showing different mobilities on SDS-PAGE (50 and 53 kDa). P450 CMLd was a good catalyst for S-mephenytoin 4'-hydroxylation in a reconstituted system. Anti-P450 2C9 antibody inhibited the activity of S-mephenytoin 4'-hydroxylase, but not the activities of R-mephenytoin 4'-hydroxylase and R- and S-mephenytoin N-demethylases in liver microsomes from cynomolgus monkeys. From these lines of evidence we conclude that P450 CMLd is classified into the P450 2C subfamily and acts as one of the S-mephenytoin 4'-hydroxylases in hepatic microsomes of cynomolgus monkeys.

Amino Acid Sequence↗
PubMed1994

Effects of sympathetic stimulation, with and without previous alpha 1 and beta adrenoceptor blockade, on refractoriness dispersion in canine heart.

OBJECTIVE: The aim was to determine the electrophysiological effects of cardiac sympathetic stimulation, with and without prior alpha 1 and beta adrenoceptor blockade during myocardial ischaemia in dogs. METHODS: Chloralose anaesthetised dogs were studied 2 h after ligation of the obtuse marginal branches of the circumflex artery (OMB). The refractory period was measured at eight sites in the ischaemic zone, two sites in the border zone, and two sites in the normal zone with S1-S2 extrastimulus methods. RESULTS: In group 1 (n = 13), before OMB ligation, stimulation of the ventrolateral cardiac nerve shortened the refractory period only in the ischaemic zone (p < 0.01). OMB ligation resulted in a significant shortening of the refractory period in the ischaemic zone (p < 0.01). In group 2 (n = 12), the alpha 1 blocker bunazosin (0.2 mg.kg-1, intravenously) blunted the shortening of the refractory period in the ischaemic zone induced by OMB ligation (p < 0.01), resulting in a reduction in refractory period dispersion between the ischaemic and non-ischaemic (border and normal) zones. Subsequent administration of the beta blocker propranolol (0.2 mg.kg-1, intravenously) prolonged refractory periods both in the ischaemic and in the non-ischaemic zones (p < 0.05 v p < 0.001). Ventrolateral cardiac nerve stimulation reversed the effects of bunazosin on the refractory period in the ischaemic zone; however, after the addition of propranolol, neural stimulation no longer influenced the refractory period. In group 3 (n = 13), propranolol (0.2 mg.kg-1, intravenously) reversed the shortening of the refractory period in the ischaemic zone (p < 0.01) induced by OMB ligation but also prolonged the refractory period in the non-ischaemic zone (p < 0.001); refractory period dispersion between the ischaemic and non-ischaemic zones was thus not reduced. Ventrolateral cardiac nerve stimulation had no effect on refractory period after administration of propranolol alone or propranolol followed by bunazosin. CONCLUSIONS: Although an alpha 1 blocker may be better than a beta blocker in reducing refractory period dispersion between the ischaemic and non-ischaemic myocardium, a beta blocker may protect more effectively than an alpha 1 blocker against the detrimental effects of cardiac nerve activity on electrical instability in the ischaemic myocardium.

Adrenergic alpha-Antagonists↗
PubMed1994

Immunochemical evidence for the occurrence of Mu class glutathione S-transferase in human fetal livers.

Immunoblot analysis showed that alpha-class glutathione S-transferase (GST), which is one of the major forms in adult human liver, was expressed in human fetal liver. Mu-class GST was also expressed in fetal liver. The majority of mu-class GST expressed in adult liver consisted of a subunit with a molecular weight of 27 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), whereas two subunits of 27 and 26 kDa were detected in fetal liver as proteins immunochemically related to mu-class GST. On reverse-phase HPLC, these two subunits cross-reactive with antibodies to rat GST 3-3 in fetal liver were indistinguishable from each other in their retention time; though, they could be separated by chromatofocusing analysis. The molecular weights of GSTs immunochemically related to rat GST 3-3, eluted at pH 7.1, 6.4, and 5.7, were 27, 27 and 26, and 26 kDa, respectively. In addition, the N-terminal amino acid sequence of these subunits suggested that GSTs related to rat GST 3-3 expressed in fetal liver may be homodimeric and heterodimeric proteins. As expected, pi-class GST was found to be a major form of GST in fetal liver but not in adult liver. In contrast, the GST immunochemically related to rat GST Yrs-Yrs, which is classified as theta-class GST, was detected in adult liver but not in fetal liver. These results indicate that several isoenzymes of GST are expressed in human fetal liver, but they are not the same as those in adult liver.

Amino Acid Sequence↗
PubMed1994

Characterization of a gene responsible for the Na+/H+ antiporter system of alkalophilic Bacillus species strain C-125.

An alkali-sensitive mutant, 38154, of the alkalophilic Bacillus sp. strain C-125 could not grow at an alkaline pH. The nucleotide sequence of a 3.7 kb parental DNA fragment that recovers the growth of 38154 at alkaline pH has four open reading frames (ORF1-4). By subcloning the fragment, we demonstrated that a 0.25 kb DNA region is responsible for the recovery. Direct sequencing of the mutant's corresponding region revealed a G to A substitution. The mutation resulted in an amino acid substitution from Gly-393 to Arg of the putative ORF1 product, which was deduced to be an 804-amino-acid polypeptide with a molecular weight of 89,070. The N-terminal part of the putative ORF1 product showed amino acid similarity to those of the chain-5 products of eukaryotic NADH quinone oxidoreductases. Membrane vesicles prepared from 38154 did not show membrane potential (delta psi)-driven Na+/H+ antiporter activity. Antiporter activity was resumed by introducing a parental DNA fragment which recovered the mutant's alkalophily. These results indicate that the mutation in 38154 affects, either directly or indirectly, the electrogenic Na+/H+ antiporter activity. This is the first report which shows that a gene responsible for the Na+/H+ antiporter system is important in the alkalophily of alkalophilic microorganisms.

Amino Acid Sequence↗
PubMed1994

Properties of two different Na+/H+ antiport systems in alkaliphilic Bacillus sp. strain C-125.

Na+/H+ antiport was studied in alkaliphilic Bacillus sp. strain C-125, its alkali-sensitive mutant 38154, and a transformant (pALK2) with recovered alkaliphily. The transformed was able to maintain an intracellular pH (pHin) that was lower than that of external milieu and contained an electrogenic Na+/H+ antiporter driven only by delta psi (membrane potential, interior negative). The activity of this delta psi-dependent Na+/H+ antiporter was highly dependent on pHin, increasing with increasing pHin, and was found only in cells grown at alkaline pH. On the other hand, the alkali-sensitive mutant, which had lost the ability to grow above pH 9.5, lacked the delta psi-dependent Na+/H+ antiporter and showed defective regulation of pHin at the alkaline pH range. However, this mutant, like the parent strain, still required sodium ions for growth and for an amino acid transport system. Moreover, another Na+/H+ antiporter, driven by the imposed delta pH (pHin > extracellular pHout), was active in this mutant strain, showing that the previously reported delta pH-dependent antiport activity is probably separate from delta psi-dependent antiporter activity. The delta pH-dependent Na+/H+ antiporter was found in cells grown at either pH 7 or pH 9. This latter antiporter was reconstituted into liposomes by using a dilution method. When a transmembrane pH gradient was applied, downhill sodium efflux was accelerated, showing that the antiporter can be reconstituted into liposomes and still retain its activity.

Alanine↗
PubMed1994

Aztreonam decreases hepatic microsomal cytochrome P450 in cynomolgus monkeys.

We examined the effect of successive administrations of aztreonam, which is used clinically as an antibiotic, on the mixed function oxidase system in non-human primates. Treatment of cynomolgus monkeys with aztreonam at doses of between 40 and 300 mg/kg for 4 weeks resulted in a significant decrease in the content of hepatic microsomal P450. On the other hand, no significant change was observed in hepatic cytochrome b5 content and NADPH-cytochrome c (P450) reductase activity following treatment with aztreonam. The activity of testosterone 6 beta-hydroxylase, but not 2 beta- and 16 alpha-hydroxylases in hepatic microsomes, was decreased following the treatment of cynomolgus monkeys with aztreonam. The content of P450 CMLc, which is classified into the 3A subfamily, was also decreased by aztreonam treatment although the content of P450 CMLb, which is a 2A enzyme in cynomolgus monkeys, was unchanged. From these results, we concluded that aztreonam decreased P450 CMLc in hepatic microsomes of cynomolgus monkeys.

Animals↗
PubMed1994

Purification and characterization of cytochrome P450 3A enzyme from hepatic microsomes of untreated doguera baboons.

We isolated a form of cytochrome P450 (P450) from hepatic microsomes of untreated doguera baboons. The final preparation (referred to as P450 BLa) was apparently homogenous, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The estimated minimum molecular weight of P450 BLa was 50 kDa. The N-terminal amino acid sequence of P450 BLa (identified 10 residues) was identical with that of P450 3A8 purified from cynomolgus monkeys. This protein was cross-reactive with antibodies raised against P450 3A4 and P450 CMLc which were P450 3A enzymes purified from hepatic microsomes of humans and cynomolgus monkeys, respectively. P450 BLa was capable of catalyzing testosterone 6 beta-hydroxylation and zonisamide reduction. P450 BLa antibody inhibited the activity of testosterone 6 beta-hydroxylase, but not the activities of testosterone 16 alpha- and 16 beta-hydroxylases in liver microsomes of doguera baboons. From these lines of evidence we conclude that P450 BLa can be classified as part of the P450 3A subfamily and acts as a constitutive testosterone 6 beta-hydroxylase in hepatic microsomes of doguera baboons.

Amino Acid Sequence↗
PubMed1994

Involvement of a cytochrome P4502D subfamily in human liver microsomal bunitrolol 4-hydroxylation.

The oxidative metabolism of bunitrolol, an adrenergic beta-receptor antagonist was examined in human liver microsomes fortified with an NADPH-generating system. The microsomal fractions (n = 11) showed bunitrolol 4-hydroxylase activities, which correlated well with CYP2D6 contents (correlation coefficient, r = 0.854), debrisoquine 4-hydroxylase (r = 0.953) and imipramine 2-hydroxylase (r = 0.976) activities. On the other hand, the bunitrolol 4-hydroxylase activity showed relatively poor correlations with CYP3A4 content (r = 0.552) and testosterone 6 beta-hydroxylase activity (r = 0.668). The bunitrolol 4-hydroxylase activity was significantly inhibited by quinidine, a selective inhibitor for CYP2D6. Polyclonal antibodies raised against rat liver microsomal cytochrome P450BTL, which is thought to belong to the CYP2D subfamily, effectively inhibited bunitrolol 4-hydroxylation. In contrast, polyclonal antibodies raised against human liver microsomal CYP3A4 did not show any inhibitory effect on the activity. These results suggest that CYP2D6 is involved in the bunitrolol 4-hydroxylase activity in human liver microsomes.

Adolescent↗
PubMed1994

[Microwave tumor coagulation (MTC) in liver tumor: indication and percutaneous approach].

Indications for microwave tumor coagulation (MTC) and percutaneous approach in liver tumor were investigated. The study population comprised 26 patients with unresectable liver tumor (4 with hepatocellular carcinoma, 22 with metastatic liver tumor) who underwent MTC at our department after April 1990. Concomitant therapies were alcohol injection in 2 patients, hepatectomy in 12 and selective arterial chemotherapy in 20. Percutaneous MTC was performed on 2 patients with a single lesion under general anesthesia. Following tip coagulation electrode penetration under echo guidance, the lesion was thermally coagulated at 60W. To establish indications for MTC by the effect of thermal coagulation, survival periods were compared by underlying disease, number of masses coagulated, and maximum tumor size, in 23 patients who had undergone MTC at least 1 year previously. Thirteen of these 23 survived for 1 year or longer, including all 3 with hepatocellular carcinoma, 3 with breast cancer, 2 with leiomyosarcoma (gastric, small intestine), 4 of the 10 with colon cancer and 1 of the 2 with pancreatic cancer. According to evaluation of the degree of coagulation, complete coagulation was obtained in 11 of 23, all of whom had at most 6 tumor masses (of up to 3 cm in diameter) coagulated, and 9 of whom survived for 1 year or longer. Percutaneous MTC, of low invasiveness, proved useful as a tool of regional cancer therapy.

Breast Neoplasms↗
PubMed1994

[Relationship between the converting ability of liver microsomes and monocrotaline-induced pulmonary hypertension in male, female and castrated male rats].

It is well known that the initial reaction of monocrotaline-induced pulmonary hypertension in rats (MPH) is injury to the endothelial cells of pulmonary vascular bed by monocrotaline-pyrrole (MP), which is converted from monocrotaline (M) by cytochrome P450 monooxygenase in hepatic microsomes. It is also known that the degree of MPH differs between sexes. The mechanisms of MPH remain, however, to be elucidated. The purpose of this study is to clarify the relationship between the converting ability of hepatic microsomes and the sexual difference in MPH using castrated male rats. A 40 mg/kg dose of M was given to fifteen 6 week-old male, twelve 6 week-old female and fifteen 6 week-old castrated male, Sprague-Dawley, rats. The castration was done at three weeks of age. Four weeks after M administration, the right ventricular systolic pressure (RVSP) and the right ventricular to total ventricular weight ratio (RV/T) were measured as indices of pulmonary hypertension. Livers were taken from six 6 week-old male, six, 6 week-old female and six 6 week-old castrated male, Sprague-Dawley, rats and then homogenized and centrifuged to extract hepatic microsomes. M, at 3.3 mM, was added to concentrated hepatic microsomes (0.25 to 1.5 mg/ml) in order to produce MP. The concentration of the MP was measured using a modification of Mattock's method. The mean value of RVSP was 86.5 mmHg in males, 59.6 mmHg in females and 73.9 mmHg in castrated males. The mean value of RV/T was 0.453 in males, 0.358 in females and 0.403 in castrated males.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Differential role in lipid peroxidation between rat P450 1A1 and P450 1A2.

The role of cytochrome P450 (P450) in lipid peroxidation induced by NADPH or peroxide was investigated in a reconstituted system. When cumene hydroperoxide, t-butyl hydroperoxide and hydrogen peroxide were used as initiators, the rates of malondialdehyde (MDA) formation were much higher in a reconstituted system containing P450 1A1 than those observed in a reconstituted system containing P450 1A2. In contrast to peroxide-induced lipid peroxidation, P450 1A2 catalysed NADPH-induced lipid peroxidation more effectively than did P450 1A1 regardless of the presence of ADP-Fe(NO3)3. Carbon monoxide inhibited NADPH-induced formation of MDA in a reconstituted system containing P450 1A2, but not P450 1A1. In addition, superoxide dismutase (SOD) was an effective inhibitor in a NADPH-induced lipid peroxidation system catalysed by P450 1A2 but not by P450 1A1. These results suggest that a peroxide-induced reaction might proceed readily with P450 1A1, whereas P450 1A2 mainly functions in NADPH-induced lipid peroxidation via generation of an active oxygen species. It is furthermore indicated that the difference in the effect of SOD in NADPH-induced lipid peroxidation depends on the P450 used.

Animals↗
PubMed1993

Involvement of CYP2D6 in oxidative metabolism of cinnarizine and flunarizine in human liver microsomes.

Oxidative metabolism of cinnarizine (CZ) and its fluorine derivative flunarizine (FZ), both of which are selective calcium entry blockers, was examined in human liver microsomes. The ring-hydroxylations and the N-desalkylations constituted primary metabolic pathways in microsomal metabolism of CZ and FZ. Among these pathways, the ring-hydroxylase (p-hydroxylation) activities at the cinnamyl moiety of both drugs were highly correlated with debrisoquine 4-hydroxylase activity and CYP2D6 content. Quinidine, a selective inhibitor of CYP2D6, suppressed the ring-hydroxylase activities of CZ and FZ. These results suggest that CYP2D6 is involved in the ring-hydroxylation of the cinnamyl moiety of both CZ and FZ in human liver microsomes.

Biotransformation↗
PubMed1993

Purification and characterization of two forms of hepatic microsomal cytochrome P450 from untreated cynomolgus monkeys.

Two forms of cytochrome P450, referred to as P450 CMLb and P450 CMLc, were purified and characterized from hepatic microsomes of untreated cynomolgus monkeys (Macaca irus). The final preparations were apparently homogeneous as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The minimum molecular weights of P450 CMLb and P450 CMLc estimated from the mobilities on the gel were 48 and 50 kDa, respectively. The N-terminal amino acid sequences of P450 CMLb and P450 CMLc (first 13 residues) were identical, respectively, with those of P450 FI isolated from baboons and P450 MK-2, which has been characterized as a P450 3A enzyme in cynomolgus monkeys. P450 CMLb showed coumarin 7-hydroxylation and 7-ethoxycoumarin O-deethylation activities. This P450 enzyme reacted with anti-P450 2A6 antibody and acts as a coumarin 7-hydroxylase in hepatic microsomes. On the basis of these results P450 CMLb was classified into the 2A subfamily. P450 CMLb is expressed constitutively as one of the minor forms of P450 in liver microsomes of untreated cynomolgus monkeys and is inducible by phenobarbital. P450 CMLc reacted with anti-P450 3A4 antibody and hydroxylated testosterone at the 6 beta-position. The testosterone 6 beta-hydroxylation activities in hepatic microsomes of cynomolgus monkeys, common squirrel monkeys, and humans were strongly inhibited by the anti-P450 CMLc antibody. These results demonstrate that this P450 enzyme is in the P450 3A subfamily.

Amino Acid Sequence↗
PubMed1993

Effects of bunazosin, a selective alpha 1-blocking agent, and propranolol used alone and in combination on canine ventricular refractoriness and its dispersion during myocardial ischemia.

The individual and combined effects of bunazosin, a selective alpha 1-adrenergic blocking agent, and propranolol on ventricular refractoriness and its dispersion were assessed in 33 chloralose-anesthetized, sympathectomized, and vagotomized dogs 2-3 h after occlusion of the obtuse marginal branches of the circumflex artery. The refractory period was measured in eight sites of the ischemic zone, two sites of the border zone, and two sites of the normal zone with S1-S2 extrastimulus methods. In group 1 dogs (n = 9), coronary artery ligation significantly shortened refractoriness in the ischemic zone (p = 0.023-0.001 in each site). Intravenous (i.v.) administration of a low dose of bunazosin at 0.1 mg/kg significantly blunted the shortening of refractoriness in the ischemic zone (p = 0.026-0.002 in each site), although the values did not reach those observed in the nonischemic zones (both the border and normal zones), where refractoriness remained unchanged. In group 2 dogs (n = 11), a higher dose of i.v. bunazosin, 0.5 mg/kg, significantly blunted the shortening of the refractory period within the ischemic zone (from 149 +/- 14 to 175 +/- 8 ms; mean +/- SD, p < 0.001) and reached the levels of the nonischemic zones (border zone 175 +/- 15 ms, normal zone 170 +/- 14 ms), resulting in a dispersion reduction in refractoriness between the ischemic and nonischemic zones. This dispersion tended to increase again with i.v. administration of 0.2 mg/kg propranolol (ischemic vs. border zone p = 0.034; ischemic vs. normal zone p = 0.089).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗