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971.
Protein kinase C has been implicated as a cellular target for Pb2+ toxicity. We have previously proposed that Pb2+ modulates PKC activity by interacting with multiple sites within the enzyme. In order to further characterize the Pb-PKC interactions we compared the effects of Pb2+ on the CA-dependent and -independent protein kinase C isozymes using recombinant human PKC-alpha, PKC-epsilon, and PKC-zeta as well as the catalytic fragment of bovine brain protein kinase C, the PKC-M. The results demonstrate that, whereas at pM concentrations Pb2+ activates PKC-alpha half maximally (KAct approximately 2 pM), it has no effect on PKC-epsilon, PKC-zeta, or PKC-M activities. The activation of PKC-alpha by Pb2+ is additive with Ca2+ in a manner indicating interaction with half of the calcium activation sites. In the micromolar range of concentrations, Pb2+ inhibits all PKCs with estimated K0.5 of 1.0, 2.3, 28, and 93 microM for PKC-M, PKC-alpha, PKC-epsilon, and PKC-zeta, respectively. Examination of Pb2+ effects on PKC-M kinetics indicates a mixed type inhibition with respect to ATP and noncompetitive inhibition with respect to histone. Taken together with the results of our previous study (Tomsig and Suszkiw, J. Neurochem. 64, 2667-2673, 1995) and the evidence for the existence of two Ca2+ coordination sites Ca1 and Ca2 within the C2 domain (Shao et al., Science [Washington, D.C.] 273, 248-251, 1996), the results of the current study provide further support for a multisite Pb-PKC interaction scheme wherein lead (1) partially activates the enzyme through pM-affinity interactions with the Ca1 site and inhibits the divalent cation-dependent activity through nM-affinity interactions with Ca2 site in the C2 domain and (2) inhibits the constitutive kinase activity through microM-affinity interactions with the catalytic domain. The concentration dependence of the differential effects of Pb2+ on the calcium-dependent and -independent PKCs underscores the importance of the C2 motif as a high affinity molecular target for Pb2+. 相似文献
972.
Gene cloning and sequencing of BmK AS and BmK AS-1, two novel neurotoxins from the scorpion Buthus martensi Karsch. 总被引:1,自引:0,他引:1
Based on the known amino acid sequences of BmK AS and BmK AS-1, the gene specific primers were designed and synthesized for 3' and 5' RACE (Rapid Amplification of cDNA Ends). Their partial cDNA fragments obtained by 3' and 5' RACE were cloned and sequenced, and the full length cDNA sequences of BmK AS and BmK AS-1 were then completed by overlapping their two partial cDNA sequences, respectively. The predicted amino acid sequences both consist of 85 amino acid residues including a putative signal peptide of 19 residues and a mature toxin of 66 residues. They are different in 17 amino acid residues, among them 11 residues in the mature toxin. The predicted amino acid sequences of BmK AS and BmK AS-1 were almost consistent with those determined and revised (personal communication), only different in one and two residues at their COO-terminal parts, respectively. Based on the determined cDNA sequences, and using the total DNAs isolated from the scorpion venom glands as a template, the genomic DNAs of BmK AS and BmK AS-1 were also amplified by PCR and sequenced. It showed that no intron was inserted in their open reading frames, while in the exon of signal peptide sequences of other Na+, K+ and Cl- channel toxins from the same scorpion, an intron is usually found. However, the Northern blot hybridization results indicated that the sizes of their mRNA should be around 800 bp. Their extra sequences around 400 bp which might function as an intron should be located at their 5' untranslated regions. 相似文献
973.
Molecular characterization of a new excitatory insect neurotoxin with an analgesic effect on mice from the scorpion Buthus martensi Karsch. 总被引:3,自引:0,他引:3
Y M Xiong Z D Lan M Wang B Liu X Q Liu H Fei L G Xu Q C Xia C G Wang D C Wang C W Chi 《Toxicon》1999,37(8):1165-1180
Besides the neurotoxins active on mammals, a new excitatory insect selective toxin with a mice analgesic activity was found and purified from the venom of the scorpion Buthus martensi Karsch (BmK) (Ji, Y.H., Mansuelle, P., Terakawa, S., Kopeyan, C., Yanaihara, N., Hsu, K., Rochat, H., 1996. Toxicon 34, 987; Luo, M.J., Xiong, Y.M., Wang, M., Wang, D.C., Chi, C.W., 1997. Toxicon 35, 723.). This peptide (designated as BmK IT-AP) is composed of 72 amino acid residues. Its primary structure was determined by automated Edman degradation of the N-terminal part of the reduced and S-carboxamidemethylated protein and its lysylendopeptidase degraded fragments. Based on the determined sequence, the gene specific primers were designed and synthesized for 3' and 5' RACE (rapid amplification of cDNA ends). Their partial cDNA fragments obtained by 3' and 5' RACEwere cloned and sequenced and the full length cDNA sequence of BmK IT-AP was then completed by overlapping their two partial cDNA sequences. It encodes a precursor of 90 amino acid residues: a signal peptide of 18 residues and a mature peptide of 72 residues which are consistent with the determined protein sequence of BmK IT-AP. The genomic DNA of the peptide was also amplified by PCR from the scorpion genomic DNA and sequenced, which is a first report on the genomic structure of a scorpion toxin specific for insects. Its sequence revealed an intron of 590 bp inserted in the end part of the signal peptide. The peptide caused a fast excitatory contraction paralysis on house fly larvae. Furthermore, the peptide also showed an obvious analgesic effect on mice, as assayed by using a twisting test model. This effect of BmK IT-AP well characterized at molecular level is first reported among the known scorpion insect neurotoxins. 相似文献
974.
975.
In our previous work, we found that the biliary excretion of the carboxylate form of irinotecan, CPT-11, on rat bile canalicular membrane consists of two components, the low-affinity one being canalicular multispecific organic anion transporter (cMOAT). In the present study, we have investigated the high-affinity component by studying the uptake in canalicular membrane vesicles. The ATP-dependent uptake of the carboxylate form of CPT-11 was inhibited significantly by several substrates and/or modulators of P-glycoprotein, including PSC-833, verapamil, and cyclosporin A, at a substrate concentration of 5 microM, at which the high-affinity component is involved predominantly in CPT-11 transport. When the concentration of the carboxylate form of CPT-11 was 250 microM, at which the low-affinity component (cMOAT) is involved predominantly in its transport, the inhibitory effect of the above compounds was reduced greatly. Similarly, there was also much lower inhibition of the ATP-dependent uptake of S-(2,4-dinitrophenyl)-glutathione, a substrate of cMOAT, by the above compounds. Taurocholic acid, a substrate of canalicular bile acid transporter, failed to inhibit the uptake of CPT-11 at the substrate concentration of both 5 and 250 microM. These results suggest that P-glycoprotein may act as the high-affinity component in the biliary excretion of the carboxylate form of CPT-11 in rats. 相似文献
976.
Correlation of biliary excretion in sandwich-cultured rat hepatocytes and in vivo in rats. 总被引:5,自引:0,他引:5
X Liu J P Chism E L LeCluyse K R Brouwer K L Brouwer 《Drug metabolism and disposition》1999,27(6):637-644
The relationship between biliary excretion in sandwich-cultured rat hepatocytes and in vivo in rats was examined. The biliary excretion of seven model substrates in 96-h sandwich-cultured rat hepatocytes was determined by differential cumulative uptake of substrate in the monolayers preincubated in standard buffer (intact bile canaliculi) and Ca2+-free buffer (disrupted bile canaliculi). Biliary excretion in vivo was quantitated in bile duct-cannulated rats. The biliary excretion index of model substrates, equivalent to the percentage of retained substrate in the canalicular networks, was consistent with the percentage of the dose excreted in bile from in vivo experiments. The in vitro biliary clearance of inulin, salicylate, methotrexate, [D-pen2,5]enkephalin, and taurocholate, calculated as the ratio of the amount excreted into the bile canalicular networks and the area under the incubation medium concentration-time profile ( approximately 0, approximately 0, 4.1 +/- 1.0, 12.6 +/- 2.2, and 56. 2 +/- 6.0 ml/min/kg, respectively), correlated with their intrinsic in vivo biliary clearance (0.04, 0, 17.3, 34.4, and 116.9 ml/min/kg, respectively; r2 = 0.99). The model compound 264W94 was not excreted in bile either in vivo or in vitro. The glucuronide conjugate of 2169W94, the O-demethylated metabolite of 264W94, was excreted into bile in vitro when 2169W94, but not 264W94, was incubated with the monolayers; 2169W94 glucuronide undergoes extensive biliary excretion after administration of 264W94 or 2169W94 in vivo. Biliary excretion in long-term sandwich-cultured rat hepatocytes correlates with in vivo biliary excretion. The study of biliary excretion of metabolites in the hepatocyte monolayers requires consideration of the status of metabolic activities. 相似文献
977.
X K Liu W Wang S N Ebert M R Franz A Katchman R L Woosley 《Journal of cardiovascular pharmacology》1999,34(2):287-294
Recent clinical observations indicate that female gender is associated with a higher risk of developing torsades de pointes (TdP) cardiac arrhythmia. In this study, we used the Langendorff technique in isolated perfused rabbit hearts and the whole-cell patch-clamp technique in ventricular myocytes to examine the gender difference in TdP incidence and gain insight into the underlying mechanisms. Isolated rabbit hearts were perfused by using the Langendorff technique. TdP was induced by abrupt changes of cycle length (deltaCL) in the presence of Tyrode's solution containing 1 mM 4-aminopyridine (4AP) and 50% reduced Mg2+ and K+ (low K/Mg). The effects of 1 mM 4AP on cardiac potassium currents were characterized by using the patch-clamp technique. Results demonstrated that (a) no significant gender difference was observed in the absolute QT interval before or after 4AP perfusion in the presence of low K/Mg; (b) 4AP caused marked QT prolongation in the ECG; (c) a significantly higher TdP incidence (nine of 12) was found in female hearts compared with male hearts (three of 12; p < 0.05); (d) 1 mM 4AP primarily inhibited Ito, although a slight inhibition of IKr also occurred in low-K/Mg Tyrode's solution. (e) No inhibition of IK1 was observed. (f) No gender difference was found in the potassium current block produced by 4AP. Female gender is associated with a higher incidence of TdP in an experimental isolated heart model and mechanisms subsequent to QT prolongation may contribute to such a gender difference. 相似文献
978.
The efficacy of the temporary oxygen carrier perflubron emulsion (PFC) in maintaining oxygen delivery, tissue oxygenation, high-energy phosphates (HEPs), and myocardial function was investigated during low-flow ischemia. Perfusion rate, oxygen tensions, and cardiac function were measured during stabilization (5 min), controlled-flow (22 ml/min x 20 min), and low-flow (0.22 ml/min x 120 min) periods in isolated rabbit hearts. Hearts were perfused with Krebs-Henseleit (KH) solution (Control), or 10 or 20% PFC (vol/vol; n = 8 per group) 5 min before and throughout the low-flow period. Myocardial tissue was then frozen for biochemical and metabolic measurements. Myocardial oxygenation was measured at incremental flow rates by using 20% PFC (n = 4) or KH (n = 6). In PFC hearts, oxygen delivery and intramyocardial tissue Po2 were improved at all evaluated time points and flow rates, respectively (p < 0.05). In Control hearts, left ventricular end-diastolic pressure was elevated at 60, 90, and 120 min of low-flow ischemia (p < 0.05). Tissue lactate was higher (p < 0.05) and HEPs lower (p < 0.05) in Control hearts during low-flow ischemia. These results indicate that PFC treatment improves myocardial oxygenation, maintains HEPs, prevents ischemic contracture, and may increase the margin of safety during low-flow ischemia in isolated rabbit hearts. 相似文献
979.
Steady state pharmacokinetics of morphine (M), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were investigated in 6 patients with intractable cancer pain administered orally with MST (Mundipharma, Limburg, Germany) and, subsequently, rectally with MSR to make a judgment whether orally administered morphine can be replaced by rectally administered morphine. The parent drug and glucuronide metabolites were measured simultaneously using high-performance liquid chromatography (HPLC) and native fluorescence detection. The mean morphine area under the curve (AUC) value (0-8 h) was smaller (434.3 +/- 170.2 nmolL(-1)h) in the oral administration than in the rectal administration (574.8 +/- 285.0 nmolL(-1)h) (p < 0.05). The rectal administration resulted in less production of M3G and M6G. There were no significant differences in the mean steady state concentrations (C(ss)) of morphine, M3G, and M6G between the oral and rectal administrations (p > 0.05). The median AUC ratio--M3G/M and M6G/M, 12.58 and 1.85--following MSR rectal administration was smaller than following MST oral administration in 6 patients (19.97 and 2.59; p < 0.05), whereas the median AUC ratio M3G/M6G in the rectal dosing was 6.24 (range 5.2-7.6) was almost the same as the median ratio M3G/M6G in the oral dosing was 6.49 (range 5.8-8.5; p > 0.1). Four of the 6 patients had a greater Cmax of M3G and M6G after oral administration than after rectal administration. The same 4 had lower fluctuation rates for morphine, M3G (p < 0.05), and M6G (p < 0.05) after rectal administration. Therefore, during chronic morphine treatment, it still seems difficult to decide whether oral administration can be replaced by rectal administration. 相似文献
980.
褪黑激素对大鼠大脑皮层脑片在缺氧后羟自由基及乳酸脱氢酶生 … 总被引:2,自引:0,他引:2
目的 研究褪黑激素对大鼠大脑皮层脑片在缺氧后羟自由基及乳酸脱氢酶生成的影响。方法 通过水杨酸捕获法一观察缺氧再给氧中自由基含量的变化,脑片通以91.6%,N2+8.4%O2造成缺氧。LDH用细胞毒检测盒测定。结果:DHBA水平在缺氧及再给氧后显著升高,缺氧时给予褪黑激素可以浓度依赖性地降低再给氧15min时DHBA的含量,但对缺氧30min时DHBA的含量没有显著作用,LDH的含量在缺氧后1h内持 相似文献