Biomedical subjects

T Horie

Publications and source records attributed to T Horie.

At least 199 records · Page 11Linked to original sources

PubMed1997

Amelioration of methotrexate-induced malabsorption by vitamin A.

Methotrexate (MTX) induces damage to the small intestine, resulting in malabsorption and diarrhea. We found that the coadministration of vitamin A (VA) with MTX protected the small intestine from MTX-induced damage. In this study, the permeability of D-glucose, D-xylose and L-leucine through the small intestine of rats treated with MTX and/or VA was studied using everted segments of small intestine. MTX treatment decreased permeability and VA coadministration prevented the decrease. The transport of D-glucose in the small intestine of MTX plus VA- and VA-treated rats and of control rats followed Michaelis-Menten kinetics, in contrast to the transport kinetics in MTX-treated rats. The pharmacokinetics of orally administered [14C]-D-glucose in control rats and MTX- and/or VA-treated rats was also studied. The bioavailability of D-glucose in MTX-treated rats was lower than in the other three groups. VA coadministration improved the bioavailability of D-glucose. Thus, it seems likely that VA ameliorates MTX-induced malabsorption.

Administration, Oral↗

PubMed1997

Receptor-dependent G protein-mediated Ca2+ sensitization in canine airway smooth muscle.

To determine the mechanisms of receptor-dependent Ca2+ sensitization in airway smooth muscle, canine tracheal smooth muscle (CTSM) was permeabilized with alpha-toxin or beta-escin. Although the effects of 5-hydroxytryptamine (100 microM), histamine (100 microM), and the thromboxane A2 analogue U-46619 (100 microM) were negligible, carbachol (100 microM) and endothelin-1 (ET-1, 1 microM) evoked additional contractions of 47.0 +/- 5.90% and 25.0 +/- 5.37% (n = 6) at pCa 6.7 with GTP (3 microM) (normalized to the maximum contraction at pCa 4.5) in alpha-toxin-permeabilized CTSM. GDP-beta-S (1 mM) reversed the carbachol and ET-1 responses completely. GTP-gamma-S (30 microM) and 4 beta-phorbol 12,13-dibutyrate (PDBu, 3 microM) increased the Ca2+ sensitivity (median effective pCa) of contraction by 1.8- and 4.4-fold, respectively (n = 4-11, P < 0.05). The effects of saturating concentrations of GTP-gamma-S and PDBu were additive. A synthetic peptide (T2) corresponding to the actin-binding site of calponin caused a dose-dependent contraction of beta-escin permeabilized CTSM, with the peak effect (25 +/- 4%, n = 4) at 1200 microM, PDBu (3 microM) caused contraction of the T2 peptide-treated CTSM. In conclusion, Ca2+ sensitization of CTSM depends on receptor type and is mediated by G proteins and protein kinase C whose effects are additive, with a partial contribution by calponin.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1997

Covalent binding of a reactive metabolite derived from propranolol and its active metabolite 4-hydroxypropranolol to hepatic microsomal proteins of the rat.

Repeated administration of propranolol (PL) to rats causes the inhibition of cytochrome P450-2D (P450-2D) enzyme. We recently found that 4-hydroxypropranolol (4-OH-PL) was biotransformed to 1,4-naphthoquinone (1,4-NQ) by superoxide (SO) anions in medium containing rat liver microsomes and NADPH and proposed that the binding of the quinone to P450-2D apoproteins might be one of mechanisms for the enzyme inhibition [Narimatsu et al. (1995) Chem. Res. Toxicol. 8, 721-728]. In this study, we have searched for possible sources of SO for the conversion of 4-OH-PL to 1,4-NQ in rat liver microsomes and determined the radioactivity covalently bound to microsomal proteins after incubation of radioactive PL and 4-OH-PL with rat liver microsomes. Elimination of 4-OH-PL from a mixture containing microsomes and NADPH was suppressed by carbon monoxide. Antibodies raised to P450-2B1 and -3A2 partially, and antibody against NADPH-cytochrome P450 reductase (fp2) markedly suppressed the reaction. 1,4-NQ was formed concomitantly with 4-OH-PL elimination by a reconstituted preparation of fp2. Binding studies using naphthalene ring (NR)- and side chain (SC)-radiolabeled PL and 4-OH-PL showed that radioactivity covalently bound to microsomal proteins was much higher from 4-OH-PL than from PL for the NR-labeled compounds, but higher from PL than from 4-OH-PL for the SC-labeled compounds. These results suggest that the 4-OH-PL formed from PL by P450-2D enzyme is converted to 1,4-NQ with loss of the side chain, and the 1,4-NQ accounts for most of the radioactivity covalently bound to microsomal proteins, including the P450-2D enzymes. The SO for conversion of 4-OH-PL to 1,4-NQ is supplied mainly by fp2 with some contribution by P450 enzymes.

Adrenergic beta-Antagonists↗

PubMed1997

TNF-alpha regulates GM-CSF-, IL-3- or M-CSF-induced Fc epsilon RII/CD23 gene expression and soluble Fc epsilon RII release by human monocytes.

The authors examined the regulatory effects of tumour necrosis factor-alpha (TNF-alpha) on granulocyte macrophage colony stimulating factor (GM-CSF)-, interleukin-3 (IL-3)- or macrophage colony stimulating factor (M-CSF)-induced gene expression of the low affinity receptor for IgE (Fc epsilon RII) on human monocytes and GM-CSF-, IL-3- or M-CSF-induced soluble Fc epsilon RII (sFc epsilon RII) release from monocytes. The expression of GM-CSF-, IL-3- or M-CSF-induced Fc epsilon RII on the surface of monocytes was reduced by TNF-alpha. The present analysis was designed to examine whether or not TNF-alpha could suppress GM-CSF-, IL-3- or M-CSF-induced Fc epsilon RII messenger RNA (mRNA) expression and enhance the release of sFc epsilon RII induced by these cytokines. The addition of TNF-alpha to monocyte cultures with GM-CSF, IL-3 or M-CSF significantly reduced Fc epsilon RII expression on the surface of monocytes and significantly increased sFc epsilon RII release from monocytes. These results suggest that TNF-alpha-dependent reduction of GM-CSF-, IL-3- or M-CSF-induced Fc epsilon RII expression on the surface of monocytes resulted, at least in part, from the suppression of Fc epsilon RII mRNA and the enhancement of sFc epsilon RII release.

Antibodies, Monoclonal↗

PubMed1997

Absorption, distribution, metabolism and excretion of a new, 14C-labelled oxazolidinone MAO-A inhibitor in rat and dog.

1. After oral administration of 14C-labelled (5R)-3-[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5-metho xymethyl -2-oxazolidinone (E2011) at a dose of 1 mg/kg, the blood level of radioactivity reached a maximum concentration (Cmax) of 0.545 microgram eq./ml after 0.25 h in the rat and of 0.900 microgram eq./ml after 0.5 h in the dog. In dog plasma, Cmax for radioactivity and unchanged E2011 were 0.862 microgram eq./ml and 0.650 microgram/ml respectively with corresponding Tmax (time at Cmax) of 0.75 and 0.25 h. The unchanged drug in dog plasma was below the detection limit (5 ng/ml plasma) after 24 h. 2. The tissue levels of radioactivity were measured at 0.25 (Tmax), 6, 24, and 168 h after administration to the rat and at 0.5 (Tmax), 24, and 168 h in the dog. The radioactivity was distributed in all tissues examined at Tmax in the rat and dog. The radioactivity levels of the cerebral cortex in the rat and dog were 26 and 36% of the plasma level at Tmax. The radioactivity in tissues decreased at almost the same rate as that in plasma. Plasma protein binding of the unchanged drug in the rat in vitro were about 70% in the range of 0.1-10 micrograms/ml, and those in the dog were about 45% in the same concentration range. 3. Cumulative excretion of radioactivity in the rat was 74.5% in urine and 22.5% in faeces after 7 days. In the dog, 55.5 and 36.5% of the radioactivity administered were excreted in urine and faeces respectively after 7 days. The biliary excretion of radioactivity in the cannulated rat was 23.0% within 48 h. 4. In tlc analysis of plasma and tissues of the rat and dog, the radioactivity for the unchanged drug was much higher than metabolites. In tlc analysis of urine, the same metabolites were detected in the rat and dog, and the radioactivity of a metabolite, IM1, was the highest in the both animals. Eight metabolites were detected in the plasma, tissues and excreta of the rat, and four metabolites in the dog. 5. In conclusion, the absorption, distribution, metabolism and excretion of 14C-labelled E2011 in the rat and dog have been established, and only minor differences were observed between these species.

Absorption↗

PubMed1997

Identification of the metabolites of a new oxazolidinone MAO-A inhibitor in rat.

1. Six metabolites present in rat urine after the oral administration of E2011 ((5R)-3-[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5-meth oxymethyl-2- oxazolidinone) were isolated with an Amberlite XAD-4 column and hplc, and termed HPM-1, HPM-2, HPM-31, HPM-32, HPM-33 and HPM-4. 2. To determine the correspondence of the findings of the metabolites between tlc (which was used in our previous study) and hplc, the six metabolites were isolated from rat urine after the administration of 14C-labelled E2011 with an Amberlite XAD-4 column and hplc, and then analysed by tlc. HPM-1, HPM-2, HPM-31, HPM-32, HPM-33 and HPM-4 were identified as IM7, IM3, IM4, IM2, IM1 and E2011, respectively. 3. The structures of the metabolites were identified with nmr and mass spectrometry. One of the compounds identified, HPM-4, was the unchanged drug, E2011, and HPM-2 was O-desmethyl-E2011. Another metabolite (HPM-33), the main metabolite in the urine, was identified as (4S)-hydroxy-E2011, and the others were (4S)-hydroxy-O-desmethyl-E2011 (HPM-1), 2"-hydroxy-E2011 (HPM-31) and (4R)-hydroxy-E2011 (HPM-32). 4. In conclusion, the main metabolic pathway of E2011 in the rat consisted of O-demethylation and hydroxylation.

Animals↗

PubMed1997

Expression of aldosterone synthase cytochrome P450 (P450aldo) mRNA in rat adrenal glomerulosa cells by angiotensin II type 1 receptor.

Changes in the mRNA levels for aldosterone synthase cytochrome P450 (P450aldo or CYP11B2) in rat adrenal glands were studied in response to angiotensin II type 1 (AT1) and type 2 (AT2) receptor antagonists. Since 11 beta hydroxylase P450 (P45011 beta or CYP11B1), which shows high homology (88.5%) with P450aldo in their nucleotide sequences of the amino acid coding regions, is also expressed in the adrenal gland, RT-PCR was performed with specific primers for each P450. Upon sodium restriction (5 mmol Na+/kg of diet) of the rats for 14 days, the amount of the P450aldo mRNA in the adrenal glands increased 8.5 fold above from the rats fed on a normal diet (225 mmol Na+/kg of diet), whereas no significant change of the P45011 beta mRNA was observed after the dietary sodium restriction. As shown by an immunoblot analysis, the adrenal capsule portions (mainly zona glomerulosa) of the rats kept on the low Na diet for 14 days expressed significantly higher level of P450aldo than those from the rats fed the normal diet. In concert with the alteration, plasma aldosterone concentration increased. However, when a specific AT1 antagonist E4177 was given to the rats kept on a low Na diet, the amount and activity of P450aldo as well as the plasma aldosterone concentration was suppressed. On the other hand, the increase of P450aldo induced by the low Na diet was not affected by an AT2-specific antagonist, PD123177.

Aldosterone↗

PubMed1997

Detection of Epstein-Barr virus-encoded small RNA 1 and latent membrane protein 1 in synovial lining cells from rheumatoid arthritis patients.

Several investigators have demonstrated an association between Epstein-Barr virus (EBV) and the pathogenesis of rheumatoid arthritis (RA). However, there is no direct evidence that this virus exists in the synovial cells of patients with RA. We attempted to detect EBV in synovial cells from RA patients. Specimens of synovial tissues from 34 patients with RA and from 20 patients with osteoarthritis (OA), and from one patient with psoriatic arthritis as controls, were examined for evidence of the EBV by in situ hybridization. The specimens were also tested by immunoperoxidase staining for expression of the CD21 molecule (EBV receptor), EBV nuclear antigen (EBNA)-2 and latent membrane protein (LMP)-1. EBV-encoded small RNA-1 (EBER) was demonstrated in synovial lining cells from eight (23.5%) out of 34 RA patients but in none of 20 OA patients (P < 0.05) nor in the one psoriatic arthritis patient. Interestingly, EBER localized in synovial lining cells that were located at the apex of villus proliferating lesions. Furthermore, LMP-1 was also detected in synovial lining cells at the top of villus lesions. Nevertheless, CD19 and CD21 molecules, and EBNA-2 were not demonstrated in such lesions. The incidence of EBV-positive in synovial lining cells with severely infiltrated lymphocytes tended to be higher than that in moderately infiltrated ones. This is the first evidence that EBV exists in chronically inflamed synovial lining cells of human joints in RA.

Antigens, Viral↗

PubMed1997

N-acetylcysteine attenuates TNF-alpha-dependent reduction of IL-4-induced Fc epsilon RII expression in human monocytes.

We have previously shown that tumor necrosis factor-alpha (TNF-alpha) reduces interleukin-4 (IL-4)-induced Fc epsilon RII expression in human monocytes. It has been shown that TNF-alpha activates nuclear transcriptional factors through the generation of reactive oxygen intermediates (ROIs), and antioxidant N-acetylcysteine (NAC) inhibits TNF-alpha-induced activation of nuclear transcriptional factors. Therefore, we hypothesized that TNF-alpha-dependent reduction of IL-4-induced Fc epsilon RII expression in monocytes might be mediated through the ROIs-activated mechanism. In the present study, to test our hypothesis, we examined the effect of NAC on TNF-alpha-dependent reduction of IL-4-induced Fc epsilon RII expression in human monocytes. NAC attenuated TNF-alpha-dependent reduction of IL-4-induced Fc epsilon RII expression by attenuating TNF-alpha-dependent reduction of Fc epsilon RII mRNA expression. Similarly, the structurally unrelated antioxidant, pyrrolidine dithiocarbamate (PDTC), also effectively attenuated this-reduction. These results indicate that an ROIs-activated and antioxidant-sensitive mechanism might be involved in TNF-alpha-dependent reduction of IL-4-induced Fc epsilon RII expression in monocytes.

Acetylcysteine↗

PubMed1997

Comparative studies on schistosomulicidal activity of mouse and rat eosinophils.

Eosinophils from interleukin (IL)-5 transgenic mice were shown to have antibody-dependent killing activity against the larvae of Schistosoma japonicum. However, in comparison with rat eosinophils, the schistosomulicidal activity of mouse eosinophils was lower. Flow cytometric analysis of the cells binding to mouse immunoglobulins demonstrated that rat cells were superior to mouse cells in the binding of mouse IgG. However, the adherence and schistosomulicidal activity of mouse cells were inhibited by rat anti-mouse Fcgamma receptor monoclonal antibody. These results suggest that the mechanism of killing by mouse eosinophils is mediated by IgG antibodies.

Animals↗

PubMed1997

A case of dermatomyositis complicated by thrombotic thrombocytopenic purpura.

A 60-year-old man with dermatomyositis was admitted to our hospital because of dyspnea and hypertension. He had high fever and convulsive seizures after admission. Laboratory examinations showed hemolytic anemia, thrombocytopenia, and renal failure. A clinical diagnosis of thrombotic thrombocytopenic purpura (TTP) was made. He failed to respond to plasma exchange therapy, pulse therapy with methylprednisolone, high-dose gamma-globulin therapy, and antiplatelet therapies with ticlopidine, dipyridamole and a prostacyclin analog of beraprost sodium. He died on his 17th day in hospital. Autopsy examination revealed widespread microthrombi in his kidneys, lungs, spleen, and intestine. Only seven cases of dermatomyositis or polymyositis complicated by TTP have been cited in the literature. TTP was fatal in 6 of these 7 cases. Early diagnosis and prompt treatment may improve the outcome of TTP patients with dermatomyositis. Dermatologists should keep in mind that TTP occasionally arises as a serious complication of dermatomyositis.

Anti-Inflammatory Agents↗

PubMed1997

Kinetics of nikkomycin Z degradation in aqueous solution and in plasma.

The stability of nikkomycin Z in aqueous solution at various pH values and in the plasma of several kinds of experimental animals was studied. The degradation of nikkomycin Z in aqueous solution at pH 4 to 11.5 and in plasma was an apparent first-order reaction. The degradation rate at 37 degrees C increased with increasing pH, from 4.0 to 7.5, and decreased with increasing pH from 7.5 to 10.2. Above pH 10.2, the degradation rate was constant. The maximal rate of nikkomycin Z degradation was observed in pH 7.5 buffer solution, in which the apparent first-order rate constant (k(obs)) was 8.08 x 10(-2) h(-1) (t1/2 = 8.6 h). The degradation rate of nikkomycin Z in dog plasma at 37 degrees C was the almost same as that in pH 7.5 buffer. The rates in rat, mouse, and rabbit plasma were much greater than that in pH 7.5 buffer; the k(obs) values for rat, mouse, rabbit, and dog plasma at 37 degrees C were 1.74 x 10(-1) min(-1), 3.64 x 10(-2) min(-1), 5.10 x 10(-1) h(-1), and 6.14 x 10(-2) h(-1), respectively. The degradation rate of nikkomycin Z in rat plasma was markedly decreased when NaF, an esterase inhibitor, was added to the plasma. The findings of faster degradation rates in rat, mouse, and rabbit plasma compared with that in pH 7.5 buffer were considered to be due to an esterase in the plasma. This notion was supported by results showing the degradation rate of nikkomycin Z in porcine liver esterase solution.

Aminoglycosides↗

PubMed1997

Regulation of aldosterone synthase cytochrome P450 (CYP11B2) and 11 beta-hydroxylase cytochrome P450 (CYP11B1) expression in rat adrenal zona glomerulosa cells by low sodium diet and angiotensin II receptor antagonists.

Changes in the mRNA levels for aldosterone synthase cytochrome P450 (CYP11B2 or P450aldo) and 11 beta hydroxylase cytochrome P450 (CYP11B1 or P45011 beta) in rat adrenal glands were studied in response to angiotensin II type 1 (AT1) and type 2 (AT2) receptor antagonists. CYP11B1 and CYP11B2 genes were highly homologous (88.5%) in their nucleotide sequences of the amino acid coding regions. Reverse transcription-polymerase chain reactions (RT-PCR) which are capable of discriminating between rat CYP11B1 and CYP11B2, were performed with specific primers for each P450. Upon sodium restriction (5 mmol Na(+)/kg of diet) of rats for 14d, the amount of the CYP11B2 mRNA in the adrenal glands was increased 8.5-fold compared to that from the rats fed a normal diet (225 mmol Na(+)/kg of diet), whereas no significant change in the CYP11B1 mRNA was observed after the dietary sodium restriction. As shown by an immunoblot analysis, the adrenal capsule portions (mainly zona glomerulosa) of the rats kept on the low Na diet for 14d expressed significantly higher levels of both CYP11B2 and CYP11B1, and contained a significantly higher amount of CYP11B2 than those from the rats fed by normal diet. The activities of the CYP11B2 enzyme were also found to be increased by about 8-fold on day 14. In concert with these alterations, the plasma aldosterone concentration (PAC) increased. However, when the specific AT1 antagonist E4177 was given to rats maintained on the low Na diet, the amount and activity of CYP11B2, as well as the PAC, were suppressed. In contrast, the increase in CYP11B2 induced by the low Na diet was not affected by the AT2-specific antagonist PD123177. These results indicate that the aldosterone synthase cytochrome P450 (CYP11B2) is an ultimate target of the regulation of aldosterone biosynthesis by an AT1 receptor antagonist.

Aldosterone↗

PubMed1997

The role of microsomal beta-glucuronidase in ascorbic acid biosynthesis stimulated by xenobiotics in rats.

We (Horio et al., 1993) have reported that the stimulation of the expression of the UDPglucuronosyltransferase (UDPGT) gene played a key role in the ascorbic acid biosynthesis induced by xenobiotics, such as 3-methylcholanthrene (3MC) and phenobarbital (PB). beta-Glucuronidase catalyzes the hydrolysis of glucuronide formed by UDPGT. The role of microsomal beta-glucuronidase in ascorbic acid biosynthesis induced by xenobiotics was investigated using homozygous and heterozygous EHBRs (Eisai hyperbilirubinuria rats) which are deficient in microsomal beta-glucuronidase. Homozygous EHBRs, heterozygous EHBRs, and Sprague Dawley (SD) rats were injected intraperitoneally once with 3MC (20 mg/kg body weight), or once a day for 2 d with PB (100 mg/day kg body weight). In these three strains of rats, the hepatic level of xenobiotics-inducible UDPGT mRNA was elevated similarly by the treatment with xenobiotics. The increases of the hepatic concentration of ascorbic acid and the urinary excretion of ascorbic acid by the treatment with 3MC or PB were markedly suppressed in both EHBRs compared with those in the control SD rats. These results indicate that the microsomal beta-glucuronidase has an important role in the hepatic ascorbic acid biosynthesis induced by xenobiotics.

Animals↗

PubMed1997

[Effects of fibronectin on the monokine production by cultured-human monocytes].

The effect of fibronectin (FN) on IL-1 alpha, IL-1 beta, TNF-alpha, and IL-6 production was investigated with cultured monocytes isolated from human peripheral blood. Monokine concentrations were determined by ELISA. FN markedly stimulated the secretion of IL-1 alpha, IL-1 beta, TNF-alpha, and IL-6 from cultured monocytes. Northern blot analysis revealed the up-regulated expression of mRNA specific for each monokine on exposure of monocytes to FN. GM-CSF, IFN-gamma, and LPS synergistically enhanced FN-induced IL-1 alpha production. We further investigated the signal transduction pathways involved in FN-stimulated monokine secretion. FN-stimulated TNF-alpha secretion was markedly inhibited by either herbimycin A or genistein, inhibitors of protein tyrosine kinase (PTK), but was not affected by staurosporin, a inhibitor of protein kinase C (PKC). The results suggest that PTK is required for FN-stimulated TNF-alpha secretion. In contrast, LPS-stimulated TNF-alpha secretion was markedly inhibited by not only herbimycin A or genistein, but also staurosporin. Therefore, both PTK and PKC may be involved in LPS-stimulated TNF-alpha secretion. We also demonstrated that, in monocytes, cytoplasmic proteins of about 70 and 240 kDa were phosphorylated after FN stimulation. Our results indicate that FN may contribute to the inflammatory response of monocyte by inducing monokine production.

Cells, Cultured↗

PubMed1997

Identification of cytochrome P450 isoforms involved in citalopram N-demethylation by human liver microsomes.

Studies to assess the enzyme kinetic behavior and to identify the cytochrome P450 (CYP) isoform(s) involved in the major metabolic pathway (N-demethylation) for citalopram (CIT), a selective serotonin reuptake inhibitor, were performed using human liver microsomes and cDNA-expressed human cytochrome P450 isoforms. The N-demethylation activities showed significant correlations with the alpha- and 4-hydroxylation activities of triazolam (r(s) = 0.818 and 0.851, respectively; P < .01) in 10 different human liver microsomes. Anti-CYP3A antibodies and ketoconazole strongly inhibited CIT N-demethylation. In addition, there was a significant correlation between CIT N-demethylation and (S)-mephenytoin 4'-hydroxylation (r(s) = 0.773, P < .05), although little inhibition was observed in the presence of anti-CYP2C antibodies or (S)-mephenytoin. cDNA-expressed CYP3A4 and CYP2C19 catalyzed CIT N-demethylation, whereas no appreciable activities were observed for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6 and CYP2E1. The percentage contributions of CYP3A4 and CYP2C19 to the overall N-demethylation of CIT in human liver microsomes were estimated using a relative activity factor; respective values of 70% and 7% were calculated for microsomes obtained from livers from putative extensive metabolizers for (S)-mephenytoin 4'-hydroxylation. These results suggest that CYP3A4 is the major isoenzyme and CYP2C19 is the minor form involved in the major metabolic pathway for CIT in human liver microsomes.

Aryl Hydrocarbon Hydroxylases↗

PubMed1997

Carrier-mediated active transport of the glucuronide and sulfate of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) into rat liver: quantitative comparison of permeability in isolated hepatocytes, perfused liver and liver in vivo.

The hepatic uptake of glucuronic acid and sulfate conjugates of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040), a dual inhibitor of 5-lipoxygenase and thromboxane A2 synthetase, was investigated in rats. The biliary excretion clearance values for the glucuronide and the sulfate, obtained after i.v. administration of E3040, were similar and corresponded to approximately 30% of the hepatic blood flow rate. The influx clearance values of E3040 conjugates in the presence of 3% bovine serum albumin, measured by a multiple indicator dilution method in the perfused liver, were 1.20 ml/min/g liver for the glucuronide and 0.74 ml/min/g liver for the sulfate, which were twice and equal to the normal hepatic plasma flow rate, respectively, which suggests the presence of an efficient transport system(s). The uptake of E3040 conjugates into the isolated hepatocytes is mediated by Na(+)-independent active transport system(s), which is inhibited by dibromosulfophthalein and bile acids. The uptake for the sulfate had high-affinity and high-capacity transport activity (Km = 25 microM; Vmax = 7.8 nmol/min/10(6) cells) compared with that for the glucuronide (Km = 59 microM; Vmax = 2.2 nmol/min/10(6) cells). The uptakes of E3040 conjugates (glucuronide, sulfate) exhibited a mutual competitive inhibition. It is suggested that both conjugates share a multispecific organic anion transporter located on the sinusoidal membrane.

Animals↗

PubMed1997

[Three cases of malignant lymphoma that developed from the chest wall].

Chronic tuberculous pyothrax and the development of non-Hodgkin's lymphoma (NHL) on the chest wall are believed to be closely related. We encountered three patients with NHL involving the chest wall in whom the tumor may have had a different origin Patient 1: A 65-year-old man with a history of pulmonary tuberculosis and right-sided pyothrax at the age of 28 years was found to have a tumor on the right sided of the chest wall, and NHL was diagnosed. Patient 2: A 65-year old woman with a history of right-sided tuberculous pyothrax at the age of 2 years had a left-sided chest-wall tumor, and NHL was diagnosed. Patient 3: A 78-year-old man with a history of tuberclous pleuritis on the left side at the age of 77 years was found to have a left-sided chest-wall tumor, and NHL was diagnosed. In patients 1 and 2, the Epstein-Barr virus was found in tissue specimens by in situ hybridization. These findings suggest that chronic tuberculous pyothrax and the development of NHL on the chest wall were not closely related in these patients, and that the Epstein-Barr virus may play an important role in the development of NHL on the chest wall after tuberculous pyothrax.

Aged↗