Search PubMed⌕ Search

Biomedical subjects

T Yokoi

Publications and source records attributed to T Yokoi.

At least 109 records · Page 6Linked to original sources
PubMed1998

Inhibition of intestinal microflora beta-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats.

PURPOSE: SN-38, a metabolite of irinotecan hydrochloride (CPT-11), is considered to play a key role in the development of diarrhea as well as in the antitumor activity of CPT-11. We have previously found that the inhibition of beta-glucuronidase, which hydrolyzes detoxified SN-38 (SN-38 glucuronide) to reform SN-38, in the lumen by eliminating the intestinal microflora with antibiotics, markedly ameliorates the intestinal toxicity of CPT-11 in rats. In this study we compared the disposition of CPT-11 and its metabolites in rats treated with and without antibiotics. METHODS: Rats were given drinking water containing 1 mg/ml penicillin and 2 mg/ml streptomycin from 5 days before the administration of CPT-11 (60 mg/kg i.v.) and throughout the experiment. CPT-11, SN-38 glucuronide and SN-38 concentrations in the blood, intestinal tissues and intestinal luminal contents were determined by HPLC. RESULTS: Antibiotics had little or no effect on the pharmacokinetics of CPT-11, SN-38 glucuronide or SN-38 in the blood, or in the tissues or contents of the small intestine, which has less beta-glucuronidase activity in its luminal contents. In contrast, antibiotics markedly reduced the AUC1-24 h of SN-38 (by about 85%) in the large intestine tissue without changing that of CPT-11, and this was accompanied by a complete inhibition of the deconjugation of SN-38 glucuronide in the luminal contents. CONCLUSIONS: These results suggest that SN-38, which results from the hydrolysis of SN-38 glucuronide by beta-glucuronidase in the intestinal microflora, contributes considerably to the distribution of SN-38 in the large intestine tissue, and that inhibition of the beta-glucuronidase activity by antibiotics results in decreased accumulation of SN-38 in the large intestine.

Administration, Oral↗
PubMed1998

Preclinical approach for identifying drug interactions.

Pharmacokinetic drug interactions may be divided into two categories: induction and inhibition of enzymes involved in the metabolism of a drug. The induction and inhibition of such enzymes result in decreases or increases in the blood concentrations of the drug, causing drug effects to be altered. Cytochrome P450 (P450 or CYP) is an enzyme responsible for the metabolism of a wide variety of drugs, including some anticancer agents. If a drug with a high affinity to bind to a specific form of P450 is given to a patient in combination with other drugs mainly metabolized by this enzyme, the former may potentiate the pharmacological actions of the latter by preventing their metabolism and thus increasing their serum concentration. Alternatively, if a drug inhibits or inactivates essentially all forms of P450 nonspecifically, it may be possible that the pharmacological effects of other drugs used in combination with it will be enhanced. CYP3A4 is one of the major forms of P450 in human liver microsomes. In previous studies using human liver microsomes, docetaxel was determined to be metabolized mainly by this isozyme. Thus it was assumed that inducers and inhibitors of CYP3A4 might affect the pharmacokinetics of docetaxel. In our studies, administration of dexamethasone, a known inducer of CYP3A, to mice resulted in decreases in serum docetaxel concentrations. In contrast, ketoconazole, an inhibitor of CYP3A, is assumed to increase the serum and hepatic concentrations of docetaxel. As an example of a drug which might inhibit the metabolism of other drugs, we found that bis-aceto-ammine-dichloro-cyclohexylamine platinum(IV) (JM216), which is currently being developed as a potential anticancer agent, inhibits essentially all major forms of P450 present in human liver microsomes. Since its inhibition potency is relatively high, careful assessment of the effects of this drug on the metabolism of other drugs appears to be necessary.

Animals↗
PubMed1998

Genetic polymorphism of drug metabolizing enzymes: new mutations in CYP2D6 and CYP2A6 genes in Japanese.

Genetic polymorphism of drug metabolizing enzymes, particularly cytochrome P450(CYP), is an important cause of adverse drug reactions. Multiple gene mutations in CYP have been shown to be phenotype. The occurrence of genetic polymorphism has been seen in genes for CYP1A1, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A5. This review discusses the molecular mechanism of two genetic polymorphisms, debrisoquine/sparteine (CYP2D6) coumarin (CYP2A6) polymorphisms. In addition, elucidation of gene mutations of CYP2D6 and CYP2A6 in Japanese will be discussed.

Aryl Hydrocarbon Hydroxylases↗
PubMed1998

Solitary fibrous tumour: significance of p53 and CD34 immunoreactivity in its malignant transformation.

AIMS: To clarify the association of p53 and CD34 expression with development of malignant solitary fibrous tumour we have studied 10 cases of solitary fibrous tumour arising in the pleura, retroperitoneum and pelvic cavity with clinicopathological features of malignancy. METHODS AND RESULTS: Tumours were localized solid masses with or without necrosis in eight and they nearly totally occupied the pleural cavity in two. Basic histology of the tumours was the proliferation of spindle cells arranged in 'patternless' pattern or in interlacing bundles with nuclear atypia and mitotic activities of various degree. In two, high-grade foci were present within low or intermediate-grade tumours. Recurrent tumours also showed more atypical features than primary tumours in two. Immunohistochemical studies showed CD34 positivity in seven, but three of them showed marked diminution or complete loss of CD34 expression in high-grade foci or a recurrent tumour. Three high-grade cases showed totally negative staining for CD34. p53 was strongly expressed in cases with fatal outcome, clinical recurrence, nuclear atypia, high mitotic activity or local invasion, whereas almost negative in benign tumours. CONCLUSIONS: Malignant solitary fibrous tumours may occur de novo or by transformation within benign or low-grade tumours and may be associated with p53 mutation. Although CD34 is a useful marker in the diagnosis of solitary fibrous tumour, one should bear in mind that its expression can be lost in high-grade tumours.

Adult↗
PubMed1998

Effect of omental lipid fraction on enhancement of skin flap survival.

The effect of an omental lipid fraction on the rate of skin flap survival in the back of the rat was assessed by planimetric and histological examination. Compared with the control group, those rats treated with the omental lipid fraction showed significant improvement of the flap survival area. On histological examination, the flap instilled with the omental lipid fraction showed vasodilatation and neovascularization between the flap and the bed. A topical application of the omental lipid fraction enhanced the skin flap survival area, and showed vasodilatation in the flap and neovascularization between the skin flap and the recipient bed.

Animals↗
PubMed1998

A new deleted allele in the human cytochrome P450 2A6 (CYP2A6) gene found in individuals showing poor metabolic capacity to coumarin and (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502).

The S-oxidation of (4)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502) and the 7-hydroxylation of coumarin are primarily catalyzed by cytochrome P450 2A6 (CYP2A6). The activities of SM-12502 S-oxidase and coumarin 7-hydroxylase were investigated with liver microsomes from 20 human individuals. Liver microsomes from individual H16 showed the lowest activities of both enzymes. The expression of CYP2A6 protein was not detectable in liver microsomes from individuals H4, H5, H7, H8, H12 and H16. CYP2A6 mRNA was hardly detectable in the liver of the individual H16. A new SacI-restriction fragment length polymorphism showing the lack of a 2.6 kb fragment was found in two of forty genomic DNA preparations from individuals H16 and No. 594, using CYP2A6 cDNA as a probe. This deletional 2.6 kb fragment was isolated from a genomic library prepared from one individuals showing normal coumarin 7-hydroxylase activity and was sequenced. This fragment contained a CYP2A6 gene region from 319 bp upstream of a putative exon 6 to a SacI site in exon 9, indicating that this region was deleted in the two individuals in this study. We also demonstrated by polymerase chain reaction analysis that the exon 8 of CYP2A6 gene was deleted in individuals H16 and No. 594. These results indicate that the reduced activity of SM-12502 S-oxidase and no activity of coumarin 7-hydroxylase are caused by the lack of CYP2A6 mRNA and CYP2A6 protein caused by the CYP2A6 gene deletion.

Aryl Hydrocarbon Hydroxylases↗
PubMed1998

Somatic mutations in the RET protooncogene in Japanese and Chinese sporadic medullary thyroid carcinomas.

Despite advances in the understanding of the genotype-phenotype correlation in multiple endocrine neoplasia type 2A and 2B (multiple endocrine neoplasia (MEN) 2A, MEN 2B), and familial medullary thyroid carcinoma (FMTC), the frequency and prognostic relevance of RET protooncogene mutations in sporadic medullary thyroid carcinomas (MTCs) remain controversial. To study somatic mutations in the RET protooncogene in Japanese and Chinese sporadic MTCs and to analyze comparatively the correlation between RET mutation and tumor differentiation, we investigated somatic mutations in the RET protooncogene in 20 Japanese and 20 Chinese sporadic MTCs by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Of the 40 sporadic MTCs, 13 had a point mutation in codon 918 of exon 16, a frequency of 32.5%. There was no significant difference in the frequency between Japanese and Chinese sporadic MTCs, as 30% of the Japanese and 35% of the Chinese sporadic MTCs contained this mutation. We did not observe any correlation between the presence or absence of codon 918 mutation and tumor differentiation in either Japanese or Chinese sporadic MTCs. Our findings indicate that the frequency of RET somatic mutations is similar in Japanese and Chinese sporadic MTCs, and the presence or absence of RET mutation does not correlate with the differentiation of sporadic MTCs.

Carcinoma, Medullary↗
PubMed1998

Overexpression of p53 protein correlates with a high risk of malignant transformation of adenomas in patients with multiple colorectal adenomas.

To assess the correlation of p53 oncoprotein expression with the high risk of developing carcinomas in patients with multiple colorectal adenomas, 25 cases with histologic carcinoma in adenoma (CIA) were examined by immunohistochemistry using a monoclonal antibody specific to human p53 protein (wild and mutant). The 25 cases were classified into multiple and single groups. The former contained 13 cases with synchronous multiple colorectal adenomas (one to six adenomas) and adenocarcinoma. The latter included 12 cases with single CIA only. This study revealed an overall incidence of 57.14% of p53 overexpression in carcinomatous lesions and 31.9% in adenomatous lesions, which was statistically significant (P < 0.05). The carcinomatous lesions showed a diffuse staining pattern, whereas the adenomatous lesions showed a focal pattern. A significant finding was that the incidence of p53 overexpression was significantly higher in multiple groups (81.25%) than in single groups (31.43%) in the carcinomatous (P < 0.01) rather than in the adenomatous (P < 0.05) lesions. There were no correlations between p53 overexpression and proliferation activity or carcinoembryonic antigen expression. The results indicate that p53 abnormality may be an important genetic factor responsible for the high risk of developing carcinomas in patients with multiple adenomas.

Adenoma↗
PubMed1998

Extensive intraductal component (EIC) and estrogen receptor (ER) status in breast cancer.

The extensive intraductal component (EIC) of primary breast carcinoma is a special spread pattern observed in the breast. Extensive intraductal component may extend diffusely over the entire breast. Therefore, EIC is considered to be an important risk factor for local recurrence in breast-conserving therapy. However, the pathogenesis of EIC remains uncertain. Whether or not the estrogen receptor (ER) has an influence on its biologic behavior has not been fully studied. A consecutive series of 142 breast carcinomas submitted to the pathology department were examined on step gross sections of 5.0 mm thick. Extensive intraductal component was determined and divided into three types. Estrogen receptor was examined using both immunohistochemistry (ER-IHC) and enzyme immunoassay (ER-EIA). Extensive intraductal component was found in 78 of 138 (56.52%) invasive carcinomas including invasive ductal carcinoma with a predominant intraductal component. Estrogen receptor-IHC positivity was 42.96% (61/142) in the invasive breast carcinoma. Estrogen receptor positivity showed no significant difference between EIC-positive and -negative cases, as well as between EIC and invasive main tumor in the EIC-positive cases. But within the EIC-positive group, ER positivity was found to be higher in the peripheral type of EIC-II and EIC-III than in the central type of EIC-I (P < 0.05). Although ER may not play an essential role in the pathogenesis of EIC, it has shown some significance in the development of peripheral type EIC because of its higher presence in the peripheral type of EIC-II and EIC-III than in the central type of EIC-I.

Antibodies, Monoclonal↗
PubMed1998

Genetic alterations in primary and secondary hyperparathyroidism.

Hyperparathyroidism refers to a term representing a wide spectrum of parathyroid disorders that are characterized by the increased production of parathyroid hormone. Hyperparathyroidism was once thought to be rare but is now more commonly recognized, affecting 1 in 500 women over 40 years of age. Yet the interpretation of parathyroid pathology is still controversial and confusing. Over the past 10 years, genetic changes (ret and menin genes) involved in the pathogenesis of MEN 2 and MEN 1 have been discovered in succession. Different mutations of the calcium-sensing receptor gene have been identified in neonatal severe hyperparathyroidism and familial hypocalciuric hypercalcemia, respectively. The HRPT 2 gene responsible for the development of hereditary hyperparathyroidism and jaw tumors has been localized on the 1q21-31 locus. Several genetic alterations have also been characterized in primary and secondary hyperparathyroidism. Different genetic alterations appear to involve the development of different types of hyperparathyroidism. These novel advances give us new insights into the pathogenesis of hyperparathyroidism and allow better differentiation between the different types of parathyroid disorders.

Adult↗
PubMed1998

SNAP-25 is essential for cortical granule exocytosis in mouse eggs.

Synaptosome-associated protein of 25 kDa (SNAP-25) has been shown to play an important role in Ca2+-dependent exocytosis in neurons and endocrine cells. During fertilization, sperm-egg fusion induces cytosolic Ca2+ mobilization and subsequently Ca2+-dependent cortical granule (CG) exocytosis in eggs. However, it is not yet clear whether SNAP-25 is involved in this process. In this study, we determined the expression and function of SNAP-25 in mouse eggs. mRNA and SNAP-25 were detected in metaphase II (MII) mouse eggs by RT-PCR and immunoblot analysis, respectively. Next, to determine the function of SNAP-25, we evaluated the change in CG exocytosis with a membrane dye, tetramethylammonium-1,6-diphenyl-1,3,5-hexatriene, after microinjection of a botulinum neurotoxin A (BoNT/A), which selectively cleaves SNAP-25 in MII eggs. Sperm-induced CG exocytosis was significantly inhibited in the BoNT/A-treated eggs. The inhibition was attenuated by coinjection of SNAP-25. These results suggest that SNAP-25 may be involved in Ca2+-dependent CG exocytosis during fertilization in mouse eggs.

Animals↗
PubMed1998

Amino acids and peptides. LII. Design and synthesis of opioid mimetics containing a pyrazinone ring and examination of their opioid receptor binding activity.

An amino group was introduced to the 3 or 6 position of a pyrazinone ring by cyclization of dipeptidyl chloromethyl ketones. Boc-Tyr-OH was coupled with the amino function, followed by removal of the Boc group to give pyrazinone ring-containing tyrosine derivatives. Of the various tyrosine derivatives prepared, 5-methyl-6-beta-phenethyl-3-tyrosylaminobutyl-2(1H)-pyrazinone exhibited strong binding to the mu-opioid receptor with a Ki value of 55.8 nM and to the delta-opioid receptor with a Ki value of 2165 nM and with a Ki mu/Ki delta value of 0.026.

Amino Acids↗
PubMed1998

[Genetic polymorphism of drug metabolizing enzymes: new mutations in CYP2D6 and CYP2A6 genes in Japanese].

Interindividual variation of drug effects in humans can be attributed to many factors. Among the factors, the rate of drug metabolism has been regarded as the most important one. A genetic defect of enzymes involved in drug metabolism, particularly cytochrome P450 (CYP), has been believed to be one of the important causal factors of adverse drug reactions. There are multiple gene mutations for CYP causing the poor metabolizer phenotype. The occurrence of genetic polymorphism has been seen in genes for CYP1A1, CYP2A6, CYP2C9, CYP2D19, CYP2D6, CYP2E1 and CYP3A5. Among them, the molecular mechanisms of genetic polymorphisms of CYP2D6 (debrisoquine/sparteine type) and CYP2A6 (coumarin type) in Japanese have been the focus of investigations. Only 20-30% of the Japanese population that shows the CYP2D6 poor metabolizer phenotype can be diagnosed by gene analysis. By other means, we found two new mutations, CYP2D6/J9 and CYP2D6/C8, in Japanese. With regard to CYP2A6, we discovered SM-12502, a new probe drug in addition to coumarin, that is currently under development; this drug is mainly metabolized by CYP2A6. Using this drug as a probe, we found poor metabolizers and analyzed the genes for CYP2A6. We found a new mutation (CYP2A6 whole deletion) responsible for the poor metabolizer phenotype. These results should contribute to the selection of an effective drug prescription and a reduced incidence of adverse effects.

Alleles↗
PubMed1998

T cell responses in EAMG-susceptible and non-susceptible mouse strains after immunization with overlapping peptides encompassing the extracellular part of Torpedo californica acetylcholine receptor alpha chain. Implication to role in myasthenia gravis of autoimmune T-cell responses against receptor degradation products.

To study the role in myasthenia gravis (MG) of peptides resulting from acetylcholine receptor (AChR) degradation, we examined the ability of AChR peptides to induce T cell responses that are capable of cross-reacting with intact AChR. The studies were carried out in an experimental autoimmune MG (EAMG)-susceptible mouse strain [C57BL/6 (B6)] as well as in two non-susceptible strains [B6.C-H-2bm12 (bm12) and C3H/He]. A set of overlapping peptides encompassing the extracellular part (residues 1-210) of the alpha-chain of Torpedo californica (t) AChR were used, individually or in equimolar mixtures, as immunogens. In B6, immunization with peptides alpha45-60, alpha111-126, alpha146-162 and alpha182-198 gave T cells that responded in vitro to the correlate immunizing peptide. Only the T cells against the latter three peptides cross-reacted with tAChR. Peptide alpha146-162 exhibited the highest in vitro reaction with the immunizing peptide and cross-reaction with tAChR. T cells obtained by immunization of B6 with an equimolar mixture of the peptides responded in vitro to peptides alpha111-126, alpha146-162 and alpha182-198 and cross-reacted very strongly with tAChR. In bm12 and C3H/He, a number of peptides evoked, when used individually as immunogens, strong or moderate T cell responses that recognized in vitro the correlate immunizing peptide but cross-reacted poorly with tAChR. Immunization with the mixture of the peptides gave T cells that recognized several peptides in each strain butdid not cross-react with alpha146-162 or tAChR. The results indicate that the ability to recognize alpha146-162 or AChR by T cells against peptides resulting from receptor degradation can account for the susceptibility to, and aggravation of, MG in B6.

Amino Acid Sequence↗
PubMed1998

[Effect of the skull on brain perfusion SPECT imaging].

Because attenuation gradually decreases reconstructed counts from the periphery to the center portion of the object, the deep region far from the detector is not clearly observed if attenuation is not compensated. In brain perfusion SPECT, diagnosis is sometimes made using filtered back projection images without attenuation compensation (FBP). Brain perfusion SPECT has the unique characteristic that the radiopharmaceutical accumulates only within the brain and is never taken up by the surrounding skull. This study investigated the effect of skull on brain perfusion SPECT reconstructed with FBP. We theoretically derived the relation between the counts of brain and the linear attenuation coefficient of skull. It was found that the difference in reconstructed counts between the deep gray matter and peripheral gray matter decreased due to the existence of the skull. This result indicated that the deep gray matter was inclined to be visible if the FBP images were displayed according to relative counts normalized to the maximum count of each image. In order to confirm this, we made a numerical phantom with realistic human brain and skull contours on the basis of MR images from a normal volunteer. The linear attenuation coefficient of brain was assumed to be 0.15 cm-1, while that of skull was assumed to be 0.26 cm-1 (denoted as BONE+) or 0 cm-1 (BONE-). In accordance with the theoretical results, the deep gray matter of BONE+ images was more clearly observed than that of BONE- images, if these were displayed using the relative counts of each images. The physical phantom experiments also supported the theoretical and numerical phantom studies.

Cerebrovascular Circulation↗
PubMed1998

Pulmonary capillary hemangiomatosis: a unique feature of congestive vasculopathy associated with hypertrophic cardiomyopathy.

A 34-year-old man with an 18-year history of hypertrophic cardiomyopathy died of worsening right-sided heart failure. Central venous pressure was greatly increased to 25 cm H2O before death. Postmortem examination revealed features of severe congestive vasculopathy, including those of pulmonary capillary hemangiomatosis in the lungs. Marked proliferation of capillaries was seen chiefly in alveolar septa and extending into pulmonary veins and arteries, causing severe luminal occlusion with recanalization. Diffusely distributed intra-alveolar edema and hemorrhage with collections of hemosiderin-laden macrophages were also seen, which suggested that the pulmonary capillary hemangiomatosis was associated with longstanding chronic passive congestion of the lung. It is possible that severe pulmonary passive congestion may be one of the causes of development of idiopathic pulmonary capillary hemangiomatosis.

Adult↗