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1.
Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT1 ) receptors in rabbit aorta and human recombinant AT1 receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'2 = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [125 I]AII binding to rabbit aortic membranes (AT, receptors) and [125 I][Sar1 , Ile8 ]AII binding to human recombinant AT1 receptors in a concentration-dependent manner with IC50 values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [125 I)AII binding to bovine cerebellum membranes (ÀT2 receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT1 receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT1 selective angiotensin receptor antagonist which exerts a competitive antagonism in the [125 I]AII binding assay and insurmountable AT1 receptor antagonism in the functional study. 相似文献
2.
Examination of potential mechanism(s) of metallothionein induction by diethyl maleate. 总被引:1,自引:0,他引:1
J W Bauman Y P Liu G K Andrews C D Klaassen 《Toxicology and applied pharmacology》1992,117(2):226-232
Diethyl maleate (DEM) is a glutathione-depleting agent that can increase the levels of the sulfhydryl-rich protein metallothionein (MT) in liver. The purpose of the present study was to examine the mechanism(s) by which DEM increases mouse hepatic MT levels. DEM appears to be an indirect MT inducer as suggested by the lack of increase in MT levels when cultured mouse hepatocytes were exposed to DEM. Four possible mechanisms by which indirect MT inducers may cause an elevation in MT concentrations in liver were examined. Zn levels did not increase prior to the increase in hepatic MT, thus, a Zn redistribution to the liver is not the cause of the liver MT induction by DEM. The adrenal gland products were not required for MT induction in liver, as adrenalectomy did not abolish the increase in hepatic MT caused by DEM. The elevation in liver MT does not appear to be due solely to the decrease in liver glutathione (60%) in the initial hour after DEM, because phorone, which decreases liver glutathione (80%), produced only a fourfold increase in hepatic MT. Activation of macrophages does not seem to account for the rise in liver MT levels, as there was no increase in abundance of cytokine mRNAs for TNF-alpha, IL-1 beta, or IL-6 in the liver. These data suggest that the induction of hepatic MT by DEM does not occur in response to (1) an increase in liver Zn that precedes the increase in liver MT, (2) release of adrenal gland products, (3) decrease in liver glutathione, or (4) increased cytokine gene expression. 相似文献
3.
W C Kershaw L D Lehman-McKeeman C D Klaassen 《Toxicology and applied pharmacology》1990,104(2):267-275
The purpose of this study was to quantitate hepatic metallothionein-I (MT-I) and metallothionein-II (MT-II) in adult mice pretreated with various dosages of selected inorganic and organic compounds and in nonchemically treated neonatal mice. Male CF-1 mice received Zn (0.38-6.0 mmol/kg, sc), Cd (5-80 mumol/kg, sc), dexamethasone (10-1000 mumol/kg, sc), or ethanol (60-180 mmol/kg, po). Liver cytosol was prepared 24 hr after the administration of each compound. In another experiment, liver cytosols were prepared from male and female neonates 1 to 35 days after parturition. MT-I and MT-II in liver cytosols were isolated by high-performance anion-exchange chromatography and quantitated by atomic absorption spectrometry. Hepatic MT-I and MT-II concentrations in adult controls were 5.1 +/- 1.3 and 3.7 +/- 1.0 micrograms/g liver, respectively. All compounds increased hepatic MT levels in a dose-dependent manner over a narrow range of dosages. The lowest dosages of Zn, Cd, dexamethasone, and ethanol that produced a significant increase in total MT content (MT-I plus MT-II) were 0.38, 0.005, 0.3, and 90 mmol/kg, respectively. Maximal induction of total MT following the highest dosages of Zn, Cd, ethanol, and dexamethasone was 58, 34, 24, and 13 times the control value (8.8 +/- 2.4 micrograms total MT/g liver), respectively. The relationship between dose and hepatic MT content was linear following ethanol administration and log-linear following Zn, Cd, and dexamethasone administration. The ratio of MT-I/MT-II was approximately 2.4 following all dosages of metals. Following low and high dosages of organic compounds, the ratio of MT-I/MT-II was approximately 1.0 and 1.5, respectively. Total MT concentration in livers of 1- to 14-day-old mice was approximately 40 times that observed in adult liver (5.5 +/- 1.6 micrograms total MT/g liver) and returned toward adult levels 21 days after parturition. The ratio of MT-I/MT-II was approximately 1.8 during Postpartum Days 1 through 14 and thereafter decreased to approximately 1.0. These results indicate that MT-I is more abundant than MT-II in mouse liver following chemical exposure and during neonatal development. 相似文献
4.
Metallothionein (MT) is a sulfhydryl-rich protein whose levels are increased by administration of a variety of agents including metals, cytokines, and oxidative stress agents. Recent studies have suggested that MT is involved in protecting against various forms of oxidative stress, but little is known about the induction of MT by oxidative stress agents. Diethyl maleate (DEM) causes oxidative stress by depleting glutathione levels and is quite effective at increasing hepatic concentrations of MT. The purpose of the current study was to learn more about the relationship between induction of MT and oxidative stress by characterizing this increase in hepatic MT levels produced by DEM. Administration of DEM (3 to 9 mmol/kg, sc) increased hepatic MT concentration in mice as much as 37-fold to 213 micrograms MT/g liver, which is similar to the hepatic MT level seen after administration of other effective MT inducers, such as Cd. The maximal increase of hepatic MT took place 12 to 24 hr after administration of 5 mmol DEM/kg. This rise in MT was preceded by a 60% depletion of hepatic glutathione 3 hr after DEM and increases in both MT-I and MT-II mRNA, which reached a peak 6 to 9 hr after DEM. Administration of DEM (3-5 mmol/kg, sc) also increased MT levels in Sprague-Dawley rats. Pretreatment with DEM protected against Cd-induced hepatotoxicity in a fashion which suggested that a functional MT was being synthesized. In summary, DEM is a highly effective inducer of MT which increases MT at the mRNA level. 相似文献
5.
Induction of multidrug resistance protein 3 in rat liver is associated with altered vectorial excretion of acetaminophen metabolites. 总被引:6,自引:0,他引:6
A L Slitt N J Cherrington J M Maher C D Klaassen 《Drug metabolism and disposition》2003,31(9):1176-1186
Treatment with the microsomal enzyme inducer trans-stilbene oxide (TSO) can decrease biliary excretion of acetaminophen-glucuronide (AA-GLUC) and increase efflux of AA-GLUC into blood. The hepatic canalicular multidrug resistance protein (Mrp) 2 and sinusoidal protein Mrp3 transport AA-GLUC conjugates into bile and blood, respectively. Thus, TSO-induced alterations in the vectorial excretion of AA-GLUC may occur via increased hepatic Mrp3 levels. The goal of this study was to determine whether TSO, diallyl sulfide (DAS), and oltipraz (OLT) treatments can up-regulate Mrp3 protein expression, and whether treatment with DAS and OLT can correspondingly increase hepatovascular efflux of AA metabolites. Rats were administered phenobarbital, TSO, DAS, OLT, or vehicle for 4 days. Interestingly, all of the chemicals increased the plasma concentration and urinary excretion of AA-GLUC and decreased its biliary excretion. In control animals, approximately 77% and 23% of AA-GLUC was excreted into bile or urine, respectively, whereas with inducer-pretreated animals, <32% of AA-GLUC was excreted into bile and >68% was excreted into urine. Correspondingly, all of the compounds increased hepatic Mrp3 mRNA levels by 13- to 37-fold and protein levels by 2- to 6-fold, respectively. In conclusion, these studies correlate increased Mrp3 protein levels in liver with increased hepatovascular excretion of AA-GLUC and suggest that induction of Mrp3 affects the route of drug excretion. 相似文献
6.
The degradation of metallothionein (MT) by rat liver was examined. Degradation of MT by liver homogenate was greater than by cytosol. In addition, MT degradation by the homogenate at pH 5.5 was more than that at pH 7.2. Because lysosomal proteases function at acidic pH, these findings suggest the importance of lysosomes in MT degradation. The degradation by the lysosomal fraction was about 400-fold greater than that by the cytosol. Because cathepsins are the principal lysosomal proteases, we used cathepsin-specific inhibitors, such as leupeptin, E-64 and pepstatin, to determine the relative importance of different cathepsins in degrading MT. The study reveals that cathepsin B and/or L is (are) probably the most important enzyme(s) in degrading hepatic MT, because leupeptin, which blocks cathepsin B and L activity, inhibited the degradation of apo-MT by about 80%. Cathepsin D appears to be of least importance in MT degradation, because inhibition of this enzyme by pepstatin reduced degradation by only 20%. Studies on the degradation of apo-MT, ZnMT, and CdMT indicated that apo-MT is about 1500-fold more sensitive to degradation than ZnMT and CdMT. These data suggest that metals protect MT from degradation. This is further supported by a reconstitution experiment, which shows that with a progressive decrease of MT: metal ratio following titration of apo-MT by metals, there is a concomitant reduction in degradation. At a lysosomal pH of around 4.7, about 60% of Zn and 20% of Cd are displaced from MT, thereby making it susceptible to degradation. We propose, therefore, that lysosomes are probably important for MT degradation in vivo and that metal release is a prerequisite for degradation. With the release of metals, MT becomes susceptible to degradation, which is probably accomplished by the lysosomal cathepsins, in particular cathepsins B and L. 相似文献
7.
8.
A 12-year-old Scottish terrier had a scrotal mass which was diagnosed as a malignant mesothelioma of the tunica vaginalis. The tumour resulted in a rapidly fatal clinical course with direct extension into the peritoneal cavity via the inguinal canal; there were no haematogenous or lymphatic metastases. This is the first case report of such a tumour in the dog. The histology and differential diagnoses of these tumours and a review of similar tumours in other species and possible causative agents are given. 相似文献
9.
Detection of chromosomes and estimation of aneuploidy in human spermatozoa using fluorescence in-situ hybridization 总被引:11,自引:0,他引:11
The development and application of fluorescence in-situ hybridization
(FISH) has opened the way for comprehensive studies on numerical chromosome
abnormalities in human spermatozoa. FISH can be rapidly applied to large
numbers of spermatozoa and thus overcomes the major limitation of
karyotyping spermatozoa after penetration of zona-free hamster oocytes. The
simultaneous hybridization of two or more chromosome-specific probes to
spermatozoa and subsequent detection of the bound probes using different
fluorescent detection systems enables two or more chromosomes to be
localized simultaneously in the same spermatozoon and provides a technique
for undertaking reasonable estimates of aneuploidy. The most commonly used
probes are those which bind to the centromeric region of specific
chromosomes. Most studies to date have concentrated on estimating
aneuploidy in spermatozoa from normospermic men, although reports are
beginning to appear on aneuploidy in spermatozoa from subfertile and
infertile men. Multi- probe FISH studies have generally reported disomy
(hyperhaploidy) estimates of 0.05-0.2% per chromosome. There is preliminary
evidence that some chromosomes such as X, Y and 21 are predisposed towards
higher rates of non-disjunction during spermatogenesis. There are also
suggestions of inter-donor variability in aneuploidy frequencies for
specific chromosomes, although this requires confirmation in larger
studies. While FISH is clearly a powerful technique that has many
applications in reproductive medicine, it must also be realized that it
does have limitations and the technology itself is still evolving and has
yet to be fully validated on spermatozoa.
相似文献
10.
Vaughan JR; Farrer MJ; Wszolek ZK; Gasser T; Durr A; Agid Y; Bonifati V; DeMichele G; Volpe G; Lincoln S; Breteler M; Meco G; Brice A; Marsden CD; Hardy J; Wood NW 《Human molecular genetics》1998,7(4):751-753
A mutation in exon 4 of the human alpha-synuclein gene was reported
recently in four families with autosomal dominant Parkinson's disease (PD).
In order to examine whether mutations in this exon or elsewhere in the gene
are common in familial PD, all seven exons of the alpha- synuclein gene
were amplified by PCR from index cases of 30 European and American
Caucasian kindreds affected with autosomal dominant PD. Each product was
sequenced directly and examined for mutations in the open reading frame. No
mutations were found in any of the samples examined. We conclude that the
A53T change described in the alpha- synuclein gene is a rare cause of PD or
may even be a rare variant. Mutations in the regulatory or intronic regions
of the gene were not excluded by this study.
相似文献