The influence of administered mass on the subcellular distribution and binding of mercury in rat liver and kidney

The influence of the administered mass on the tissue and sub-cellular distribution of mercury (Hg) was investigated in rats, using ²⁰³Hg. The fraction of the dose deposited in liver increased threefold over the dose range 0.17–1.65 mg Hg · kg^–1, while the retention in the kidney decreased by a factor of 2. The uptake in other organs, lung, spleen, brain, thymus, salivary glands showed no dose-dependent variation.Subcellular fractionation studies showed a dose-dependent increase in the Hg content of the liver cytosol, with corresponding decreases in the deposition in the lysosomal and nuclei-cell debris fractions. In contrast, no clear changes in the distribution of Hg amongst the subcellular organelles of the kidney were observed.The amount of Hg bound to metallothionein in the liver cytosol rose steeply with increasing dose. However, in the kidney cytosol the mass of Hg bound to metallothionein increased with dose up to 0.55 mg Hg · kg^–1, thereafter remaining approximately constant. These observations suggest that the Hg-binding metallothionein in the kidney was saturated by administered doses greater than 0.55 mg Hg · kg^–1, whereas in liver saturation levels of the metal were not reached even at the highest dose tested, 1.65 mg Hg · kg^–1.     

Measurement of contents in organs of selenium- or vitamin E-deficient rat using instrumental neutron activation analysis

The contents of iron (Fe), cobalt (Co), zinc (Zn), and selenium (Se) in the organs (liver, kidney, spleen, heart, lung, and brain) and the liver cell fractions (nuclear, mitochondrial, microsomal, and cytosolic fractions) of Se- or vitamin E (VE)-deficient rats were measured using instrumental neutron activation analysis (INAA). The contents of Fe in the liver of Se-deficient rats, and in the liver and the spleen of VE-deficient rats were increased compared with those in normal rats. Fe contents increased mainly in the microsomal fraction. Contents of Co in the organs and liver cell fractions of Se- and VE-deficient rats were markedly low, reflecting the Co contents in both diets. Contents of Zn in the organs and liver cell fractions of Se- and VE-deficient rats decreased to 60-80% of the contents in normal rats. The Se contents in Se-deficient rat organs except for the kidney, spleen, and brain were below the detectable level under the present conditions. Se contents in VE-deficient rat decreased to 50-80% of those in normal rats in all organs and fractions. It is suggested that oxidative stress due to Se- or VE-deficiency affects the dynamics of Fe and Zn.     

Tissue distribution of 20 nm, 100 nm and 1000 nm fluorescent polystyrene latex nanospheres following acute systemic or acute and repeat airway exposure in the rat

Understanding tissue distribution and clearance of nanomaterials following different routes of exposure is needed for risk assessment. F344 female rats received single or multiple exposures to 20 nm, 100 nm or 1000 nm latex fluorospheres by intravenous (i.v.) injection or oral pharyngeal aspiration into the airways. The presence of fluorospheres in tissues was assessed up to 90–120 days after the final dose. Blood, perfusion fluid, bone marrow, brain, eyes, feces, gut, heart, kidney, liver, lung, muscle, skin, spleen, thymus, tongue, urine and uterus plus ovaries were collected for analysis. Liver, spleen and lung were the greatest tissue depots for all particles following i.v. injection. The proportion of 100 nm and 1000 nm but not 20 nm spheres significantly increased in the spleen over time. Lung was the greatest tissue depot for all particles following single or repeat airway exposure. Greater than 95% of 1000 nm spheres that were recovered were in the lung in contrast to 70–80% of 20 nm spheres or 89–95% of 100 nm spheres. All 3 sizes were found in gut or gut + feces 1–7 days after lung exposure. The thymus was the largest extra-pulmonary depot for the particles; up to 25% of recovered 20 nm particles were in the thymus up to 4 months after exposure compared to 6% of 100 nm particles and 1–3% of 1000 nm particles. A small proportion of 20 nm particles were detected in kidney following both acute and repeat airway exposure. Low numbers of particles were found in the circulation (blood, perfusion), bone marrow, brain, heart, liver and spleen but not in eye, muscle, skin, tongue, ovaries, uterus or urine. These data show that the tissue targets of nano- and micron-sized spheres are very similar whether exposure occurs systemically or via the airways while the proportion of particles in some tissues and tissue clearance varies based on particle size.     

The apparent ubiquity of epoxide hydratase in rat organs

Using the recently developed sensitive assay with [³H] benzo [a] pyrene 4,5-oxide as substrate, epoxide hydratase was shown to be present in 26 rat (Sprague-Dawley) organs and tissues investigated. Only blood showed no detectable activity, which indicates that the low enzyme activity found in some organs is not due to the presence of blood components in the tissues. In earlier studies with a less sensitive assay, epoxide hydratase activity was detected only in rat liver and kidney but not in organs such as muscle, spleen, heart and brain. Epoxide hydratase was also measured in 6 organs of the mouse (NMRI). The distribution pattern was quantitatively quite different in the two species. The sp. act. in the rat were in the order liver > testis > kidney > lung > intestine ～- skin. In the mouse, very surprisingly, testis had the highest specific epoxide hydratase activity. Moreover, the order of sp. act. in the mouse organs was remarkably different from that in the rat, namely testis > liver > lung > skin > kidney > intestine. The fact that the sp. act. in kidney was much lower than in lung or skin is most striking. Pretreatment of rats with Aroclor 1254 (a mixture of polychlorinated biphenyls) increased the epoxide hydratase activity in the liver to 175 per cent of the control level. However, the enzyme activity in the 13 extrahepatic tissues investigated was not significantly changed. In organs possessing sufficiently high enzyme levels, epoxide hydratase activity was also measured with styrene oxide as substrate. The ratio of the sp. act. of the two substrates was very similar in rat liver, kidney, lung and lestis. This supports the assumption that in these organs a single enzyme is responsible for the hydration of both substrates—as was earlier shown by several methods for the rat liver.     

Histological analysis of 70-nm silica particles-induced chronic toxicity in mice

Nano-sized silica is a promising material for disease diagnosis, cosmetics and drugs. For the successful application of nano-sized material in bioscience, evaluation of nano-sized material toxicity is important. We previously found that nano-sized silica particles with a diameter of 70 nm showed acute liver failure in mice. Here, we performed histological analysis of major organs such as the liver, spleen, lung, kidney, brain and heart in mice, chronically injected with 70-nm silica particles for 4 weeks. Histological analysis revealed hepatic microgranulation and splenic megakaryocyte accumulation in these 70-nm silica particles treated mice, while the kidney, lung, brain and heart remained unaffected. Thus, liver and spleen appear to be the major target organs for toxicity by the chronic administration of the 70-nm silica particles.     

~(131)I标记尖吻蝮蛇毒凝血酶样酶在动物体内的分布

用氯胺T法对尖吻蝮(Agkistrodon acutus)蛇毒的抗血栓组分凝血酶样酶进行~(131)Ⅰ标记,观察其在大、小鼠体内的分布。以实验组和给予同剂量凝血酶样酶混合Na~(131)Ⅰ的对照组的放射性参入量(脏器与血液放射比)的比值作为凝血酶样酶在组织中分布的依据。结果表明,一次快速ⅳ凝血酶样酶后2h分布最多的为肾、其次为肺、脾、肾上腺和肝。给药后4h,肾、脾、肺和肝比2h时高,心脏含量较少,其它组织未见有分布。尿中含量高,表明其主要经肾脏随尿排泄;经胆汁排出则很少。     

β-榄香烯脂质体的制备及其在大鼠体内的组织分布

目的:研制β-榄香烯脂质体并考察其在大鼠体内的组织分布。方法:采用薄膜分散法制备β-榄香烯脂质体,考察其形态、粒径、Zeta电位、药物含量及包封率。并以榄香烯注射液为对照,大鼠尾静脉注射给药,考察β-榄香烯脂质体在血浆及心、肝、脾、肺、肾的分布特征。结果:制备的β-榄香烯脂质体均匀圆整,粒径为(158±s 37)nm,Zeta电位为(-67±4)mV,药物含量为(5.76±0.21)g·L~(-1),包封率为(45.08±0.15)%(n=3)。大鼠尾静脉注射β-榄香烯脂质体和榄香烯注射液后,2种制剂在心、肝、脾、肾中的AUC_(0-t)均有显著差异,其中β-榄香烯脂质体在肝、脾、肾组织中分布相对较多,在心脏中分布较少。结论:薄膜分散法制备β-榄香烯脂质体方法可行,β-榄香烯脂质体在大鼠体内的分布特性有不同程度的改变,可提高疗效,降低心脏毒性。     

Distribution of polyhexylcyanoacrylate nanoparticles in nude mice over extended times and after repeated injection

Carbon-14-labeled polyhexylcyanoacrylate nanoparticles, with diameters between 200 and 300 nm, were injected intravenously into nude mice. The distribution in liver, spleen, lung, heart, kidney, GI tract, gonads, brain, muscle, and serum was investigated by liquid scintillation counting. After a single injection, the radiolabel was cleared slowly with 45% remaining after 28 d and 8% remaining after 140 d. After repeated injection with an interval of 28 d (twice or thrice), relatively higher proportions of the dose were found in the spleen and lung as compared with those in other organs. No histological alterations were observed in the liver, spleen, or lung.     

Tissue distribution study of naringin in rats by liquid chromatography-tandem mass spectrometry

Naringin (CAS 10236-47-2), a flavanone glucoside widely present in fruits of citrus plants, has received extensive studies on its potential effects on health benefits and was recently demonstrated to be a putative antitussive. In this study, we determined the tissue distributions of naringin and its metabolites (naringenin and naringenin's conjugates) in rats to examine whether they undergo selective uptake by specific organs. Naringin was administered orally to rats at the dose of 42 mg/kg and the concentrations of naringin and its metabolites in tissue compartments were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The areas under curve values in the individual tissues decreased as follows: stomach, small intestine, liver, trachea, muscle, kidney, lung, fat, heart, spleen, ovary, testis, brain for naringin; and liver, stomach, small intestine, kidney, trachea, lung, testis, heart, ovary, fat, spleen, muscle, brain for total naringenin (including free and its conjugates). Naringin and total naringenin were rapidly and widely distributed to all the tissues except brain in rats. They had difficulties in crossing the blood-brain barrier. There are no accumulations in rats. This study identifying naringin in several organs including lung and trachea may explain its effects as antitussive.     

Increase of thiopental concentration in rat tissues due to anesthesia with isoflurane.

Thiopental distribution was studied in rats (30 mg/kg i.v.) anesthetized simultaneously with 1.25 "rat"-MAC isoflurane. The thiopental concentration in serum and several tissues was determined UV-photometrically at 305 nm after extraction and TLC. In the serum of rats anesthetized with isoflurane the thiopental concentration was significantly increased to +39----+74% in comparison to controls during 30 min following the barbiturate injection. Also in liver, brain, heart, kidney, lung and spleen of rats anesthetized with isoflurane the thiopental concentration was significantly increased at 3 and 10 min; at 30 min the difference vs. control had vanished in brain, heart, lung and spleen. Obviously, thiopental was transiently "trapped" during the early distribution phase to a considerable amount in these vessel-rich tissues when anesthesia with isoflurane was simultaneously performed; this pharmacokinetic interaction might be explained at least to some extent hemodynamically; in many tissues regional blood flow is reduced during anesthesia with isoflurane; thereby the "washout" of thiopental from the tissues and the redistribution are delayed.     

射干提取物在大鼠体内分布研究

目的研究射干提取物在大鼠体内的组织分布特征。方法射干提取物给大鼠灌药后,以鸢尾黄素为研究指标,采用高效液相色谱法测定其在大鼠心、肝、脾、肺、肾中的含量。结果鸢尾黄素在大鼠体内各部分的分布顺序为：肝〉肾〉肺〉心〉脾。结论射干提取物中鸢尾黄素在大鼠体内分布广泛,在肝肾肺组织中药物浓度较高,并且在肺组织中达到平衡后能较长时间保持药物浓度,与射干药材归肺经相符合,提示鸢尾黄素可能是射干用于治疗上呼吸道作用的药效物质之一。     

Intracellular Gene Transfer in Rats by Tail Vein Injection of Plasmid DNA

In this study, we examined the effect of various factors on gene delivery efficiency of tail vein injection of plasmid DNA into rats. We measured the level of reporter gene expression in the internal organs including the lung, heart, spleen, kidney, and liver as function of injection volume, injection time, and DNA dose. Persistency of reporter gene expression in transfected animals was also examined. We demonstrated that plasmid delivery to rats by the tail vein is effective as long as the volume of injected DNA solution is adjusted to 7–8% of body weight with an injection time of less than 10 s. With the exception of a short-term increase in serum concentration of alanine aminotransferase and transient irregularity in cardiac function during and soon after the injection, the procedure is well tolerated. Lac Z staining of the liver from transfected animals showed approximately 5–10% positive cells. Persistency test for transgene expression in animals using plasmid carrying cDNA of human alpha 1 antitrypsin gene driven by chicken beta actin gene promoter with CMV enhancers showed peak level of transgene product 1 day after the injection followed by a gradual decline with time. Peak level was regained by a second injection performed on day 38 after the first injection. These results show that tail vein injection is an effective means for introducing plasmid DNA into liver cells in rats. We believe that this procedure will be extremely useful for gene function studies in the context of whole animal in rats.Key words: gene delivery, gene therapy, hydrodynamic gene delivery, nonviral vectors, siRNA delivery     

伊曲康唑纳米粒的制备及其在小鼠体内的分布

用HPLC法测定了小鼠单剂量(20mg/kg)尾静脉注射伊曲康唑纳米粒及其市售注射剂后心、肝、脾、肺、肾、脑和血浆中的药物浓度.结果表明,伊曲康唑纳米粒在肺中的AUC为注射剂的32.94倍;在心、肾组织的蓄积量减少,在各组织中的半衰期延长,尤以肝、脾、肺为甚.说明伊曲康唑纳米粒的肺靶向性明显优于市售注射剂.     

Reactions of vinyl chloride with RNA and DNA of various mouse tissues in vivo

The irreversible binding of ¹⁴C-vinyl chloride metabolites to RNA and DNA of mouse brain, lung, liver, kidney, spleen, pancreas, and testes after a single i.p. injection has been studied. Hydrolysates of nucleic acids from selected organs were separated on Aminex A6 for quantitation of alkylation products.Radioactivity in nucleic acids was registered in all of the studied organs with the exception of brain. RNA from spleen, pancreas and liver, and DNA from spleen and liver contained the highest amounts of radioactivity. In nucleic acids from spleen and pancreas, both organs of high metabolic activity, the entire radioactivity was found metabolically incorporated as C₁-fragments. In RNA of kidney and liver, a large part of the radioactivity was also present as incorporated C₁-fragments, but 3,N⁴-ethenocytidine (in kidney) as well as 1,N⁶-ethenoadenosine and 1,N⁶-ethenoadenine (in kidney and liver) were identified as alkylation products. In liver DNA, incorporation of C₁-fragments was insignificant, indicating different interactions of vinyl chloride metabolites (C₁-fragments and alkylating products) with RNA and DNA. The elution profiles of radioactivity in hydrolysates of liver DNA were dominated by an alkylation product of unknown structure (probably a derivative of deoxyguanosine). Possibly, 1,N⁶-ethenodeoxyadenosine and 1,N⁶-ethenoadenine were also present in liver DNA.The results are consistent with the ability of vinyl chloride to act as a multipotent carcinogen by alkylation of DNA in several tissues.     

Physiologically based pharmacokinetic model of docetaxel and interspecies scaling: comparison of simple injection with folate receptor-targeting amphiphilic copolymer-modified liposomes

1.?To compare the disposition of docetaxel (DTX) in male/female rats after intravenous administration of simple injection and folate-poly(PEG-cyanoacrylate-co-cholesteryl cyanoacrylate)-modified liposomes utilising a physiologically based pharmacokinetic (PBPK) modelling method, and extrapolate this model to mice and humans by taking into account the interspecies differences in physiological- and chemical-specific parameters.

2.?Four structural models for single organs were evaluated, and the whole-body PBPK model included artery, vein, lung, brain, heart, spleen, liver, gastrointestinal tract, kidney, muscle and remainder compartment.

3.?Rats following modified liposomes administration were characterised by significant decrease in the partition coefficients for brain, spleen, liver and remainder compartment. The blood-to-plasma partition coefficient also decreased significantly, while a marked rise of partition coefficients for lung, kidney and muscle was revealed. Partition coefficient for heart was approximately 1.3-fold higher in females than males, while the decrease of intestinal clearance was revealed in females compared to males. The final model successfully characterised the time course of DTX in rats, mice and humans.

4.?This PBPK model is beneficial to the prediction of the effects of DTX in different species. It also represented a platform to encompass both formulation- and sex-related effects on DTX disposition and elimination in the future.     

Specific incorporation of labelled tissue homogenates into the homologous organs of the rat (author's transl)]

The time course of the incorporation of radioactivity into the liver, kidney, heart, spleen, lung, adrenal glands, and testes following subcutaneous application of L-histidine-2,5-T-labelled homogenates of liver, kidney and heart has been measured in 105 male Sprague-Dawley rats aged 3 months (weight: x = 350 g). The homogenates had been prepared from organs of rats of the same age, sex and weight, each labelled with 400 muCi L-histidine-2,5-T. The maximal incorporation of activity from the homogenates into the organs investigated has been found 24 h after injection. In the kidney, however, an additional peak appeared already 5 h post applicationen. The comparison of the activities of the liver, kidney and heart, taking into account the differences in organ metabolism, revealed a significantly higher incorporation into the homologous than in the non-homologous organs. This specific incorporation appeared 2 h after the injection and could be found until about 24 h. The type of labelling, the method of sample preparation and the time of absorption allowed to conclude that the specific affinity to the homologous organs might have been due to a relatively small amount of short peptides. The functional significance especially for the regeneration of impaired organs has been discussed taking into account earlier results.     

Differential retention of doxorubicin in the organs of two strains of rats

Fluorescence microscopy and high pressure liquid chromatography were used to study the decrease of doxorubicin (DXR) concentrations in the liver, spleen, heart, lung, kidney and skeletal muscle of two strains of rats at various times after a single intravenous injection of the drug (8 mg kg-1). DXR was located within the cell nucleus and was mostly undegraded, it persisted, especially in heart, lungs and spleen where it was detectable 10 days after injection. The DXR/DNA ratio, was used as an index of nuclear fixation of the drug. A major difference in the DXR/DNA ratio between the two strains were observed in heart and spleen results; the DXR/DNA ratio was significantly higher in heart and spleen compared with lung, liver and kidney in both strains.     

羟基喜树碱纳米粒在大鼠体内的药动学、组织分布及靶向性研 究

目的:研究羟基喜树碱纳米粒在大鼠体内的药动学及组织分布特征,并探讨其靶向性.方法:将雄性SD大鼠随机分为两组,每组6只,分别单剂量尾静脉注射羟基喜树碱纳米粒和市售羟喜树碱注射液(4 mg/kg,以羟基喜树碱计),在给药后5、30、60、120、240、360、480、600、720 min时于眼底静脉丛取血500μL,...     

Age-related changes in benzylamine oxidase activity in rat tissues

Brain, liver, heart, lung, kidney and duodenum benzylamine oxidase (BZAO) activities were measured from young and old rats. Protein content was found to decrease in liver (-17%), kidney (-20%) and duodenum (-17%) but remained unchanged in brain, heart and lung of old rats compared with that of young rats. A significant decrease (-41%) of BZAO activity was found in lung whereas a significant increase of enzyme activity was found in brain (+49%) and kidney (+25%) and no change was found in heart and duodenum of old rats. BZAO was not detected in either young or old rat liver. Kinetic analysis for lung BZAO activity of old rats showed that Vmax was decreased but Km was unchanged in comparison with that of young rats. Since, as we have shown previously, MAO-A and -B activity in lung of old rats was also found to be decreased, the decrease of lung BZAO activity with increasing age merits further investigation, lung playing an important role in removing amines from the circulation.     

Hepatic,intestinal and renal transport of 1-naphthol-β-d-glucuronide in mutant rats with hereditary-conjugated hyperbilirubinemia

Summary Recently, a mutant rat strain was described with a genetic defect for the biliary excretion of organic anions (TR^– rats). To determine the possible heterogeneity of the transport systems in liver, intestine and kidney we investigated the transport of the anion 1-naphthol--d-glucuronide (1-NG) in isolated vascularly perfused organ preparations of the rat liver, intestine and kidney of both Wistar rats and TR^– rats. 1-NG was administered as such (liver and kidney experiments) or formed intracellularly from 1-naphthol (1-N) (liver and gut experiments). Independent of the type of exposure to 1-NG, the biliary excretion was considerably impaired in TR^– rats. In the intestine the total appearance and the vascular/luminal distribution pattern of 1-NG were not significantly different from the values in control rats. Furthermore, no significant disturbance was found with respect to the renal clearance of 1-NG in the TR^– rat when compared with the Wistar rat. Thus, the genetic defect in the TR^– rat is restricted to an impaired hepatobiliary excretion of 1-NG and does not affect the excretory systems of the intestine and kidney. These results suggest that the excretion of 1-NG by the liver, intestine and kidney involves distinct organ-specific transport systems.