bluuebunny/crossref_metadata_2025 huggingface dataset:
Zur Stereochemie der 3‐Oxo‐5‐phenyl‐1‐cyclopentancarbonsäuren, 7. Mitt. Synthese kernfluorierter, stereomerer 5‐Phenyl‐dihydrosarkomycine, Teil 1
Authors: Körfer Inge , Frahm August W.
Published: October 2006

Bei der Synthese der 5‐(4‐Fluorphenyl)‐dihydrosarkomycine aus trans‐4‐Fluorzimtsäuremethylester (1) und Propan‐1.1.2‐tricarbonsäuretrimethylester (2) werden die Dieckmannringschlußprodukte 3 und 4 schrittweise durch saure bzw. basische Verseifung und Decarboxylierung zu den isolierbaren Zwischenstufen 9 und 10, 5 und 6, 7 und 8 und 11 und 12 abgebaut.
13C‐NMR‐spektroskopische Untersuchungen an substituierten N‐Sulfonyl‐1‐azabutadienen
Authors: Neidlein Richard , Kramer Walter , Klotz Udo J.
Published: October 2006

Es wird über die Ergebnisse der 13C‐NMR‐spektroskopischen Untersuchungen der Verbindungen 1a, 1b, 1c, 1d und 1e berichtet.
Über die Reaktion von Quadratsäure mit Carbodiimiden
Authors: Grünefeld Johann , Zinner Gerwalt
Published: October 2006

Aus Quadratsäure (5) und Carbodiimiden 2 wurden erhalten: N‐(2‐Hydroxy‐3,4‐dioxo‐1‐cyclobutenyl)‐N,N′‐dialkylharnstoffe 6 bzw. N,N′‐Diaryl‐quadratsäurediamide 8, mit N‐Isopropyl‐N'‐phenylcarbodiimid (2f) in Abhangigkeit von den Reaktionsbedingungen N‐(2‐Hydroxy‐3,4‐dioxo‐1‐cyclobutenyl)‐N'‐isopropyl‐N‐phenylharnstoff (17) bzw. 3,4‐Di(3‐isopropyl‐1‐phenylureido)‐3‐cyclobuten‐1,2‐dion (19).
Beitrag zu den Struktur‐Wirkungsbeziehungen am Acronycin
Authors: Reisch Johannes , Aly Samir M. El‐Moghazy
Published: October 2006

Die Synthese von 1b, einem Aza‐anologon des Acronycins (1a), wird beschrieben. Die Wasserlöslichkeit von 1b übertrifft die von 1a um das 15‐fache. Im Screening am Transplantationstumor Leukämie P 388 erwies sich 1b ‐ wie 1a und Noracronycin ‐ als wirkungslos. Auch die mit 1a verwandten Verbindungen 6‐Hydroxy‐3,3,12‐trimethyl‐3,12‐dihydrochromeno[5,6‐b][1,8]naphthyridin‐7‐on, 5‐Hydroxy‐2,2‐11‐trimethyl‐2,11‐dihydrochromeno[7,6‐b][1,8]naphthyridin‐6‐on sowie 6‐Hydroxy‐3,3‐dimethyl‐3H‐pyrano[2′,3′:7,8]chromeno[2,3‐b]pyridin‐7‐on sind inaktiv.
New Lanthanum (III) Complex – Synthesis, Characterization, and Cytotoxic Activity
Authors: Kostova Irena , Rastogi Vinod K. , Kiefer Wolfgang , Kostovski Aleksandar
Published: October 2006

The complex of lanthanum (III) was synthesized reacting the respective inorganic salt with 5‐aminoorotic acid in amounts equal to the metal : ligand molar ratio of 1 : 3. The complex was prepared by adding an aqueous solution of lanthanum (III) nitrate to an aqueous solution of the ligand, subsequently raising the pH of the mixture gradually to approx. 5.0 through addition of a dilute solution of sodium hydroxide. The structure of the final complex was determined by means of spectral data (IR, Raman, 1H‐NMR) and elemental analysis. Significant differences in the IR spectrum of the complex were observed as compared to the spectrum of the ligand. A comparative analysis of the Raman spectrum of the complex with that of the free 5‐aminoorotic acid allowed a straightforward assignment of the vibrations of the ligand groups involved in coordination. The ligand and the complex were tested for the cytotoxic activities on the chronic myeloid leukemia derived K‐562, overexpressing the BCR‐ABL fusion protein and the non‐Hodgkin lymphoma derived DOHH‐2, characterized by a re‐expression of the anti‐apoptotic protein bcl‐2 cell lines. The results obtained indicate that the tested compounds exerted a considerable cytotoxic activity upon the evaluated cell lines in a concentration‐dependent matter, which enabled the construction of dose‐response curves and the calculation of the corresponding IC50 values. The inorganic salt exerted a very weak cytotoxic effect on these cells, which is in contrast to the lanthanum (III) complex.
Influence of antibiotic cefotaxime on somatic embryogenesis and plant regeneration in indica rice
Authors: Grewal Deepinder , Gill Raman , Gosal Satbir Singh
Published: October 2006

An antibiotic, cefotaxime (Omnatax™) has been found to promote somatic embryogenesis and subsequent plant regeneration in vitro in indica‐type basmati rice cultures. Response was highly genotype specific. The number, mass and morphology of the calli formed on the scutellar tissues were dependent on the growth medium (with or without cefotaxime). The embryogenic nature of nodular calli was confirmed through histological analysis and their plant regeneration ability. The calli of variety Pusa basmati 1 grown on medium supplemented with cefotaxime (100 mg/L) exhibited up to 70.5% plant regeneration as compared to control (51.51%). Plants regenerated from emryogenic calli were phenotypically normal and identical to seed‐derived plants and exhibited normal fertility. A limited humidity and an optimal aeration of the culture tubes further enhanced the frequency of somatic embryogenesis and plant regeneration.
Carbon Nanotube/Poly(methyl methacrylate) (CNT/PMMA) Composite Electrode Fabricated by In Situ Polymerization for Microchip Capillary Electrophoresis
Authors: Yao Xiao , Wu Huixia , Wang Joseph , Qu Song , Chen Gang
Published: October 2006

We describe the development and application of a novel carbon nanotube/poly(methyl methacrylate) (CNT/PMMA) composite electrode as a sensitive amperometric detector of microchip capillary electrophoresis (CE). The composite electrode was fabricated by the in situ polymerization of a mixture of CNTs and prepolymerized methyl methacrylate in the microchannel of a piece of fused silica capillary under heat. The performance of this unique system was demonstrated by the separation and detection of phenolic pollutants and purines. The new CNT‐based CE detector offered significantly lower operating potentials, yielded substantially enhanced signal‐to‐noise characteristics, and exhibited resistance to surface fouling and, hence, enhanced stability. Long‐term stability and reproducibility with relative standard deviations of less than 5 % for the peak current (n=20) were also demonstrated. The simplicity and significant performance exhibited by the CNT/PMMA composite electrode indicate great promise for conventional CE, flowing‐injection analysis, and other microfluidic analysis systems.
Polyisocyanides Derived from Tripeptides of Alanine
Authors: Metselaar Gerald A. , Adams P. J. Hans M. , Nolte Roeland J. M. , Cornelissen Jeroen J. L. M. , Rowan Alan E.
Published: October 2006

Helical polymers of isocyanotripeptides derived from alanine have been synthesized and their architectures studied in detail. The helical conformation of the polyisocyanotripeptides is stabilized by internal hydrogen‐bonding arrays between the tripeptide side chains. The possibility of extending the well‐defined hydrogen‐bonded array, from dipeptide to tripeptide side chains, depends strongly on the stereochemistry of the constituent alanine amino acids, as has been shown by circular dichroism and IR studies. In polymers containing a weaker hydrogen‐bonding array adjacent to the polymer backbone, due to steric interactions between the alanine methyl groups, a stronger second hydrogen‐bonding array was present between the peptide bonds furthest away from the main chain, which is probably a result of stretching/compression of the helical‐polymer conformation.
Proapoptotic effects of NARC 1 (= PCSK9), the gene encoding a novel serine proteinase
Authors: Bingham Brendan , Shen Ru , Kotnis Smita , Lo C. Frederick , Ozenberger Bradley A. , Ghosh Nivedita , Kennedy Jeffrey D. , Jacobsen J. Steven , Grenier Jill M. , DiStefano Peter S. , Chiang Lillian W. , Wood Andrew
Published: October 2006

Background

NARC 1/PCSK9 encodes a novel serine proteinase known to play a role in cholesterol homeostasis. NARC 1 mRNA expression in cerebellar granule neurons (CGNs) was discovered to be induced following an apoptotic injury. Coregulation of known apoptotic mediators (caspase‐3 and death receptor 6) raises the possibility that NARC 1 might be involved in the propagation of apoptotic signaling in neurons.

Methods

CGNs were transfected with EGFP‐fusion constructs of wild‐type and mutant NARC 1, and a laser scanning cytometry‐based method of scoring cell death in transfectants was applied. Use of the poly‐caspase inhibitor BAF allowed assessment of the caspase‐dependence of the NARC 1 proapoptotic effect.

Results

Wild‐type NARC 1 was found to have substantial proapoptotic effects that were only partially reversible by BAF. Mutation of the active site serine or deletion of the catalytic domain resulted in a reduced level of cell death, consistent with loss of the BAF‐sensitive component of cell death. NH2‐terminal deletion constructs of NARC 1 had effects similar to wild‐type, both in the absence and presence of BAF, whereas expression of COOH‐terminal deletion mutants produced a rate of cell death similar to wild‐type in the absence of BAF treatment, but which lacked the capacity to be reduced by treatment with BAF.

Conclusion

The mechanism by which NARC 1‐EGFP over‐expression induces cell death in cultured CGNs remains unclear. Mutation analysis established a positive correlation between the presence of the Narc 1 active site serine in the transiently expressed protein and induction of the BAF‐sensitive component of the cell death phenotype. A caspase‐independent component proved sufficiently complex to map discretely within the Narc 1 protein. © 2006 International Society for Analytical Cytology
Technologies and applications of Al‐free high‐power laser diodes
Authors: Ohgoh Tsuyoshi , Fukunaga Toshiaki , Hayakawa Toshiro
Published: October 2006

We report high‐power technologies in 0.8‐µm Al‐free InGaAsP/InGaP laser diodes. To realize the high‐power operation, the improvement of catastrophic optical mirror damage (COMD) power density level is required. In addition to the use of low surface recombination velocity of Al‐free materials, optimization of waveguide thickness in broad waveguide structure with tensile‐strained barriers and current blocking structure near facets has led to high COMD power density level. Highly stable operation of Al‐free laser diodes with these structures has been obtained over 2500 hours at 2 W from a stripe width of µm. Applications of high‐power laser diodes are also described. © 2006 Wiley Periodicals, Inc. Electr Eng Jpn, 158(1): 53–59, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/eej.20286
Incoming longwave radiation to melting snow: observations, sensitivity and estimation in Northern environments
Authors: Sicart J. E. , Pomeroy J. W. , Essery R. L. H. , Bewley D.
Published: October 2006

At high latitudes, longwave radiation can provide similar, or higher, amounts of energy to snow than shortwave radiation due to the low solar elevation (cosine effect and increased scattering due to long atmospheric path lengths). This effect is magnified in mountains due to shading and longwave emissions from the complex topography. This study examines longwave irradiance at the snow surface in the Wolf Creek Research Basin, Yukon Territory, Canada (60° 36′N, 134° 57′W) during the springs of 2002 and 2004. Incoming longwave radiation was estimated from standard meteorological measurements by segregating radiation sources into clear sky, clouds and surrounding terrain. A sensitivity study was conducted to detect the atmospheric and topographic conditions under which emission from adjacent terrain significantly increases the longwave irradiance. The total incoming longwave radiation is more sensitive to sky view factor than to the temperature of the emitting terrain surfaces. Brutsaert's equation correctly simulates the clear‐sky irradiance for hourly time steps using temperature and humidity. Longwave emissions from clouds, which raised longwave radiation above that from clear skies by 16% on average, were best estimated using daily atmospheric shortwave transmissivity and hourly relative humidity. An independent test of the estimation procedure for a prairie site near Saskatoon, Saskatchewan, Canada, indicated that the calculations are robust in late winter and spring conditions. Copyright © 2006 John Wiley & Sons, Ltd.
The response of precipitation and surface hydrology to tropical macro‐climate forcing in Colombia
Authors: Marin Saul , Ramírez Jorge A.
Published: October 2006

In tropical South America, weather and climate are affected by the meridional oscillation of the inter‐tropical convergence zone, the Pacific and Atlantic oceans, the Amazon basin, and the Andes Mountains. The dominant mode of the inter‐annual climate variability in the tropical Pacific is the El Niño/Southern Oscillation (ENSO) phenomenon. Colombia is among the South American countries that experiences large climate anomalies because of ENSO. However, the hydrologic response in Colombia to a particular ENSO event is highly complex and non‐linear.

To describe this complex, non‐linear hydro‐climatic response to large‐scale atmospheric forcing in Colombia, a one‐way coupled atmospheric‐land surface hydrologic modelling approach is implemented whose main components are Colorado State University's Regional Atmospheric Modelling System (RAMS) and the Swedish Hydrologiska Byråns Vattenbalansavdelning‐Hydrologic Modelling System (HBV‐HMS). RAMS is implemented in a two‐nested grid domain for seasonal simulations and a four‐nested grid domain for daily simulations. Seasonal simulations emphasize the annual cycle at regional scales, while daily simulations focus on describing the diurnal cycle for specific watersheds. The HBV‐HMS is implemented for a specific watershed and used to examine its response at daily time scales.

Results of the seasonal simulations reproduce quite well the observed spatial and temporal patterns of the hydro‐climatic variables: simulated temperature, pressure, wind velocity, and precipitation distributions show good agreement with observations. Results also show that the 1992 warm phase of ENSO led to a generalized decrease of precipitation along the Andes ranges and that the low lands of Colombia received more precipitation than during the 1989 cold ENSO phase. Similarly, daily‐simulated fields show good agreement with observed values. However, the simulated diurnal cycle of precipitation exhibits a temporal phase lag of several hours and simulated precipitation tends to underestimate both the total amount of precipitation and the duration of precipitation events. Despite these discrepancies, the results of the modelling effort clearly demonstrate the ability of this approach to capture the non‐linear and complex interactions of large‐scale atmospheric forcing and local characteristics as indicated by the satisfactory simulation of stream flow responses for a set of small watersheds. Copyright © 2006 John Wiley & Sons, Ltd.
Chronic studies in rats exposed to liquid effluent from coal gasification process
Authors: Kostial K. , Blanuša M. , Rabar I. , Maljković T. , Kello D. , Landeka M. , Bunarević A. , Stara J. F.
Published: October 2006

The health effects of the E‐effluent (water for quenching ash) from a coal gasification plant were assayed in a chronic experiment (16 month exposure) and a three generation reproduction study. Animals exposed to 100% E‐effluent had an increased daily intake of various inorganic elements (Fe, Cu, K, I, Se, Cd, Hg, Pb, As, F and Cr). In spite of that, the exposed and control animals had the same mortality rate, haematological findings, urinary protein excretion, trace element concentrations in kidneys, liver and femur, bone composition and morphometry, and histological findings. The pre‐ and post‐natal development and growth was unchanged during three generations. It is concluded that the higher intake of various inorganics caused no change in the parameters measured.
Selective determination of elemental mercury in blood and urine exposed to mercury vapor in vitro
Authors: Satoh Hiroshi , Hursh John B. , Clarkson Thomas W. , Suzuki Tsuguyoshi
Published: October 2006

A method is described to ensure quantitative measurement of dissolved mercury vapor (Hg°) in blood and urine. Room air passed through samples of blood and urine carries with it all the dissolved Hg° but leaves behind all the ionic mercury (Hg++). Oxidation of Hg° to Hg++ in blood samples is completely inhibited by addition of ethanol (0.5% v/v). To minimize error due to evaporation of Hg°, it is suggested that samples should be stored at 0 °C and Hg° should be determined within 60 min of collection of blood samples and within 10 min of urine samples.
Alcohol and sulphate intermediates in the metabolism of toluene and xylenes to mercapturic acids
Authors: van Doorn R. , Leijdekkers Ch.‐M. , Bos R. P. , Brouns R. M. E. , Henderson P. Th.
Published: October 2006

The involvement of sequential side‐chain oxidation, sulphation and glutathione conjugation in the formation of mercapturic acids from toluene and xylenes was investigated. It was found that not only aralkanes but also aralkyl alcohols were excreted as mercapturic acids in the rat. The extent of mercapturic acid excretion varied over a more than 20‐fold range. Inhibition of ADH caused an increase and inhibition of sulphotransferase a decrease in the urinary excretion of thio compounds after administration of toluene, benzyl alcohol, o‐xylene and o‐methylbenzyl alcohol to rats. The position of the methyl groups attached to the aromatic nucleus affects the metabolism of aromatic hydrocarbons considerably. Factors that are involved in the high yield of mercapturic acids after administration of o‐xylene as compared to m‐ and p‐xylene, include the relatively low apparent affinity of o‐methylbenzyl alcohol for cytosolic ADH, the relatively high apparent affinity of o‐methylbenzyl alcohol for cytosolic sulphotransferase, and the high electrophilic reactivity of the o‐methylbenzyl sulphate.
Number connection test and continuous reaction times in non‐encephalopathic patients: A comparative study
Authors: Christensen Steen Erik , Elsass Peter , Vilstrup Hendrik
Published: October 2006

Number Connection Test (NCT) and Continuous Reaction Times (CRT) were determined in 94 hospitalized patients with no previous or actual cerebral dysfunction. By NCT, 47 patients used more than 30 s which is the upper normal limit. Of these, 5 used more than 50 s. Two patients exhibited a CRT exceeding the upper normal limit of 240 ms. Thus, accepting the upper limits quoted, one‐half of the patients were falsely classified as encephalopathic by NCT, but only 2% by CRT. This indicates that the NCT is too unspecific to exclude encephalopathy and suggests that the CRT is a more valid measure in this respect.
In vitro metabolism of inorganic arsenic by the gastro‐intestinal microflora of the rat
Authors: Rowland I. R. , Davies M. J.
Published: October 2006

The contents of the rat small intestine or caecum reduced sodium [74As] arsenate to arsenite over a period of 2–3 days. In the presence of caecal, but not small intestine, contents, small amounts of methyl arsonic acid and dimethylarsinic acid were formed. Stomach contents reduced arsenic very slowly. The metabolism of arsenate was inhibited by autoclaving the gut contents or by adding antibiotics, thus indicating that bacteria were involved. In prereduced media containing thioglycollate or cysteine in the absence of intestinal bacteria, sodium arsenate was reduced to arsenite. The rate of reduction of arsenate by the gut flora was increased by the presence of hydrogen sulphide or bile acids.
Effect of pharmacologic interventions on aldehyde dehydrogenase in the rat testicles
Authors: Messiha F. S.
Published: October 2006

The in vitro and in vivo effects of selected pharmacologic agents on cytosolic aldehyde dehydrogenase in the adult rat testicles were studied. Naltrexone, a narcotic antagonist, significantly inhibited epididymal but not testicular aldehyde dehydrogenase in vitro. Greater in vitro inhibition of aldehyde dehydrogenase in the epididymal preparation was determined in the presence of diphenyhydramine, a histamine H1‐receptor antagonist and by amantadine hydrochloride, an antiviral/antiparkinsonian agent. The latter drug also inhibited testicular aldehyde dehydrogenase from corresponding controls. The in vitro inhibition was non‐competitive as evaluated by reciprocal plots of the velocity of the reaction as a function of substrate concentrations. Short‐term oral administration of a biologically active metabolite of flutamide, a nonsteroidal antiandrogen, significantly induced testicular aldehyde dehydrogenase without concomitant changes in epididymal aldehyde dehydrogenase from respective controls. Conversely, administration of ethinylestradiol, an estrogenic steroid, inhibited testicular but not epididymal aldehyde hydrogenase in the rat.
Bio‐mimetic composite matrix that promotes endothelial cell growth for modification of biomaterial surface
Authors: Prasad C. Krishna , Muraleedharan C. V. , Krishnan Lissy K.
Published: October 2006

The incidence of thrombogenesis and occlusion of cardiovascular implants is likely to be reduced by endothelial cell (EC) growth promotion on biomaterials used for device fabrication. However, proper signaling between the matrix proteins deposited on the device surface and the cells grown on it is a prime requirement for growth and function. It was demonstrated earlier that a composition of matrix proteins that include fibrin, fibronectin, gelatin, and growth factors maintain a steady proliferation potential and prolong the survival of endothelial cells in vitro. In this study, assessment of the same matrix to prevent EC from dedifferentiation during in vitro culture and to promote endothelialization of biomaterials used for fabrication of cardiovascular implants is carried out. Up/down regulation of m‐RNA expression for a prothrombotic molecule‐plasminogen activator inhibitor (PAI), and two antithrombotic molecules‐ nitric oxide synthetase (eNOS) and tissue plasminogen activator (t‐PA) are chosen as the indicators of cell dedifferentiation during cell culture and passaging. Immunostaining for vinculin and actin demonstrated that composite coating on biomaterials improves focal adhesion and cytoskeletal organization that increases the quality of EC grown on it. EC proliferation, measured by 3H‐thymidine uptake, on all bare materials was poor and high incidence of cell apoptosis was noticed within 72 h in culture, whereas once coated with composite all materials showed good proliferation and survival. The results suggest that the designed composition of biomimetic adhesive proteins and growth factors is suitable for EC growth, survival, and functional integrity, thus making it suitable for cardiovascular tissue engineering that requires in vitro EC culture. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2007
Compressive properties and degradability of poly(ε‐caprolatone)/hydroxyapatite composites under accelerated hydrolytic degradation
Authors: Ang K.C. , Leong K.F. , Chua C.K. , Chandrasekaran M.
Published: October 2006

Hydroxyapatite (HA) was incorporated as filler into polycaprolactone (PCL) matrix to improve the bioactivity as well as the compressive properties of the polymer composites that can be typically used in tissue engineering scaffolds. The compressive properties of five PCL/HA composites of different compositions were investigated in conjunction with the study of their rate of degradation. As PCL has a slow degradation rate, the experiment was conducted in a concentrated 5M sodium hydroxide medium to accelerate the degradation process. The compressive strength and modulus of all PCL/HA compositions were observed to decrease as the degradation experiment progressed, with samples having high HA content degraded most significantly as compared with samples with lower HA content. Pure PCL samples, however, were found to retain their mechanical properties comparatively well in the same degradation experiments. Although the addition of HA as filler into the PCL matrix was shown to have improved mechanical properties and bioactivity initially, these results do raise concerns of material properties being compromise during hydrolytic degradation. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2007
An examination of the oxidation of mercury vapor by rat brain homogenate
Authors: Sichak S. P. , Mavis R. D. , Finkelstein J. N. , Clarkson T. W.
Published: October 2006

The oxidation of mercury vapor (Hg°) to divalent inorganic mercury (Hg2+) was studied in rat brain homogenates. By using a “degassing” method, it was possible to speciate the mercury present in the homogenate and, for the first time, to measure the rate of oxidation as a function of the substrate (Hg°) concentration. Mercury oxidation was first‐order with respect to substrate concentration at all concentrations tested, and the first‐order rate constant for the oxidation process was proportional to homogenate concentration. The role of catalase compound I in mercury vapor oxidation by brain homogenate was examined by observing the effects of two inhibitors of catalase (catalase compound I) on homogenate mercury‐oxidizing activity and catalase activity. Sodium azide (50 mM) completely inhibited both mercury‐oxidizing activity and catalase activity. Aminotriazole (3‐amino‐1H‐1,2,4‐triazole) (50 mM) completely inhibited only mercury‐oxidizing activity; some residual catalase activity was found in the aminotriazole‐treated homogenate. It was concluded that catalase compound I plays a major role in the oxidation of Hg°, but the possibility that catalase‐independent pathways make a minor contribution cannot be excluded.
Ah receptor for 2,3,7,8‐ tetrachlorodibenzo‐p‐Dioxin: Ontogeny in chick embryo liver
Authors: Denison Michael S. , Okey Allan B. , Hamilton Joshua W. , Bloom Stephen E. , Wilkinson Christopher F.
Published: October 2006

Aryl hydrocarbon hydroxylase (AHH, cytochrome P1‐450) is induced in chick liver very early during embryonic development if embryos are treated with 3‐methylcholanthrene–type compounds such as 3,4,3′4′‐tetrachlorobiphenyl. In mammals, AHH induction is known to be mediated by the Ah receptor. Liver from embryonic and newly hatched chicks was found to contain a cytosolic receptor for 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) which has properties that are very similar to properties of the Ah receptor previously characterized in mammalian tissues. In chick embryo liver, cytosolic binding sites for TCDD were of high affinity (Kd for [3‐H]‐TCDD = 0.2 nM) and were specific for 3‐methylcholanthrene–type inducers. The specific binding component sedimented at about 9S on sucrose density gradients prepared at low ionic strength. A high level of Ah receptor was detected in chick embryo liver by the fifth day of incubation (5 DI); this is at least 24 hours prior to the onset of AHH inducibility. The Ah receptor concentration increased from 5 DI to 8 DI, the period when chick liver is undergoing early morphological differentiation. After 8 DI, Ah receptor levels dropped substantially and remained low into the posthatching period. In contrast, AHH inducibility was high by 7 DI and remained high throughout embryonic development and into the posthatching period. The discrepancy between Ah receptor levels and the degree of AHH inducibility suggests that only a small fraction of the Ah receptor population is required for maximal AHH induction.
Methoxyacetic acid and ethoxyacetic acid inhibit mitochondrial function in vitro
Authors: Beattie P. J. , Brabec M. J.
Published: October 2006

Ethylene glycol monomethyl ether (EGME) and ethylene glycol monoethyl ether (EGEE) have recently been shown to be potent reproductive toxicants in laboratory animals. The toxicity of these compounds is believed to be due to their metabolites, methoxyacetic acid (MAA) and ethoxyacetic acid (EAA). Since the primary targets of EGME and EGEE appear to be tissues with rapidly dividing cell systems and high rates of respiration and energy metabolism, the effects of these compounds and their proposed metabolites on mitochondria were investigated. At concentrations beginning at 3.85 mM, MAA and EAA inhibited state 3 respiration and the respiratory control ratio (RCR) in hepatic mitochondria with either succinate or citrate/malate as substrates. Cytochrome c oxidase activity was also inhibited by both metabolites at similar concentrations. The effects of MAA, the metabolite from the more potent compound, on testicular mitochondria were found to be comparable. Neither EGME or EGEE appeared to affect mitochondrial function at concentrations as high as 238 or 113 mM, respectively. These results support the hypothesis that the toxicity of EGME and EGEE are due to their metabolites, MAA and EAA, and that these metabolites may exert their effects, in part, on mitochondrial function.
Cytochrome P‐450—Mediated denitrification of 2‐nitropropane in mouse liver microsomes
Authors: Marker Elizabeth K. , Kulkarni Arun P.
Published: October 2006

Enzymatic denitrification of 2‐nitropropane (2NP) was investigated in an NADPH‐dependent hepatic microsomal system from male CD1 mice. The involvement of cytochrome P‐450 (P‐450) as the catalyst in 2NP denitrification was revealed by the induction of nitrite‐releasing activity following phenobarbital (PB) pretreatment, by a decrease in activity with carbon tetrachloride pretreatment, by the inhibition of the reaction with classical P‐450 inhibitors, and by the observation of a type I binding spectrum. Under optimal conditions, two pH‐dependent peaks of activity were observed at pH 7.6 and pH 8.8, each with its own optimal substrate concentration. Inhibition of the reaction by metyrapone and carbon monoxide (CO) (among others) produced differential responses dependent on pH. These results, along with two pH optima and two substrate optima, suggested the involvement of multiple P‐450 isozymes. Average specific activities were 8.05 nmoles of nitrite released per minute per milligram microsomal protein at pH 7.6 and 6.44 nmoles of nitrite released per minute per milligram microsomal protein at pH 8.8. Acetone was identified as the second product of the reaction by gas chromatography/mass spectrometry (GC/MS). Stoichiometry studies indicated that the acetone production was slightly less than expected (about 70%) from nitrite release. Up to 25% residual activity was observed under anaerobic conditions. These results suggested that though the predominant reaction mechanism was oxidative, oxygen‐independent metabolism of 2NP also occurred to some extent. In contrast to the reported lack of activity in untreated rat, the observed denitrification in uninduced mouse liver microsomes was significant and suggested that major species‐specific differences exist in the in vitro metabolism of 2NP.
Mechanisms of petroleum hydrocarbon toxicity: Destruction of liver microsomal and mitochondrial calcium pump activities by a prudhoe bay crude oil
Authors: Khan S. , Payne J. F. , Rahimtula A. D.
Published: October 2006

Administration of Prudhoe Bay crude oil (PBCO) to rats resulted in an abrupt drop in liver mitochondrial and microsomal ATP‐dependent calcium uptake activity. Also, in vitro incubations of either mitochondria or microsomes in the presence of a dimethyl sulfoxide (DMSO) extract of PBCO resulted in a dose‐dependent inhibition of calcium influx. The release of calcium from calciumloaded mitochondria and microsomes was also observed in the presence of the PBCO extract. At concentrations which effect calcium sequestration, the PBCO extract produced swelling of mitochondria. Microsomal ATPase activity in the presence or absence of calcium was unaffected by PBCO. The results indicate that increased permeability of the membranes to calcium is a contributory factor in the inhibition of calcium uptake by PBCO.
Peroxidase, an alternate pathway to cytochrome P‐450 for xenobiotic metabolism in skin: Partial purification and properties of the enzyme from neonatal rat skin
Authors: Strohm Bradford H. , Kulkarni Arun P.
Published: October 2006

Peroxidase activity was partially purified from neonatal (3 to 6 days old) rat skin. The membrane‐bound peroxidase activity was extracted with 0.5 calcium chloride and was monitored spectrophotometrically at 470 nm with 2‐methoxyphenol (guaiacol) and hydrogen peroxide as substrates. Subcellular distribution studies indicated the activity to be highest and comparable in nuclei mitochondria, lowest in microsomes, and absent in cytosol. The peroxidase activity was partially purified by affinity chromatography on concanavalin A‐sepharose 4B and by gel filtration using Bio‐Gel P‐150. Purification factors from these two steps were about 25 and 4, respectively. Peroxidase extraction in the presence of 2mM N‐ethylmaleimide increased activity about twofold. The combination of 2 mM N‐ethylmaleimide and 10% (w/v) glycerol was found to be optimal for preservation of activity. Peroxidase activity increased linearly with increases in protein concentration, time, and guaiacol concentration. Activity was inhibited approximately 75% by 0.1 mM potassium cyanide or 0.05 mM sodium azide. Pyrogallol, hydroquinone, p‐cresol, catechol, benzidine, 3,3′‐dimethoxybenzidine, tetramethyl‐benzidine, and p‐phenylenediamine also acted as substrates for the rat cutaneous peroxidase.
Role of cellular calcium homeostasis in toxic liver injury induced by the pyrrolizidine alkaloid senecionine and the alkenal trans‐4‐OH‐2‐hexenal
Authors: Griffin Donna S. , Segall H. J.
Published: October 2006

The pyrrolizidine alkaloid senecionine has been shown to be hepatotoxic, genotoxic, and cytotoxic. However, the biochemical mechanism by which senecionine produces hepatocellular toxicity remains to be elucidated. The role of calcium homeostasis in toxic liver injury was examined in isolated rat hepatocytes treated with senecionine and trans‐4‐OH‐2‐hexenal (t‐4HH), a microsomal metabolite of senecionine, and appropriate cofactors. Hepatocytes treated with senecionine and t‐4HH demonstrated greater cytotoxicity (leakage of lactate dehydrogenase) when incubated in the absence of extracellular Ca2+ than in its presence. Both compounds elicited an increase in cytosolic Ca2+ levels of isolated hepatocytes in the presence of extracellular Ca2+ In the following study, senecionine and t‐4HH depleted intracellular glutathione levels and induced lipid peroxidation and cytotoxicity in isolated hepatocytes. Pretreatment with the thiolgroup reducing agent dithiothreitol prevented depletion of intracellular glutathione and protected hepatocytes against senecionine and t‐4HH‐induced lipid peroxidation and cytotoxicity. Both compounds also depleted intracellular ATP and NADPH levels. These results suggest that hepatotoxocity induced by senecionine and t‐4HH is not dependent on the influx of extracellular Ca2+; however, alterations in intracellular Ca2+, possibly associated with depletion of intracellular glutathione, NADPH, and ATP, may play a critical role.
Short communication effects of six months' feeding of cypermethrin on the blood and liver of albino rats
Authors: Shakoori Abdul Rauf , Ali Syed Shahid , Saleem Mushtaq A.
Published: October 2006

A cypermethrin‐mixed diet was fed uninterrupted to male albino rats for six months to evaluate toxicity in nontarget organisms. The rats consumed cypermethrin at a dose of 420 mg active ingredient (AI) per kilogram body weight per day. At the end of the stipulated period, the blood and liver were analyzed for insecticidal toxicity. The hemoglobin content and white blood cell (WBC) count remained unaltered, while the red blood cell (RBC) count and packed‐cell volume (PCV) decreased significantly. The blood serum lactate dehydrogenase (LDH), isocitrate dehydrogenase (ICDH), and amylase activities were elevated 61%, 30%, and 46%, respectively, after six months of insecticide feeding, suggesting liver and possibly pancreas malfunction. The glutamate oxaloacetate transaminase (GOT) and creatine phosphokinase (CPK) activities, on the other hand, decreased 37% and 40%, respectively. The blood serum protein and free amino acids (FAA) content increased 12% and 31%, respectively, while cholesterol content decreased 49%. Consequent to cypermethrin administration the hepatic GOT, LDH, and ICDH activities increased 250%, 20%, and 30%, respectively. The soluble proteins, FAA, and glucose contents exhibited significant increases of 28%, 61%, and 71%, respectively. Histological changes were marked by hypertrophied hepatic cells and nuclei.
Sodium arsenite induced alterations in bilirubin excretion and heme metabolism
Authors: Albores A. , Cebrián M. E. , Bach P. H. , Connelly J. C. , Hinton R. H. , Bridges J. W.
Published: October 2006

The acute administration of sodium arsenite (AsIII) to rats resulted in a biphasic alteration of the hepatic cytosolic “free” heme pool. The first stage was an increase in the cytosolic “free” heme without significant effects on the content of cytochrome P‐450 or on bilirubin excretion. The second stage consisted of a continuous fall of the cytosolic “free” heme and of the content of cytochrome P‐450. These changes were concurrent with an eight‐fold increase in heme oxygenase activity and associated with marked elevations in the biliary excretion of bilirubin. The bile was collected from chronically cannulated rats to avoid artifacts related to anesthesia or post anesthetic effects. The rapid increase in biliary excretion of labeled heme degradation products indicated an increased breakdown of newly synthesized heme. Immunoelectrophoresis of bile proteins showed an altered pattern of bile protein excretion. The increased biliary haptoglobin suggested some hemolysis, while the reduction in the free immunoglobulin A (IgA) secretory component showed an AsIII‐related decreased protein transport across hepatocytes to bile. Further research is required to assess the direct role of an increased heme degradation in the genesis of the hepatotoxic effects of AsIII.
Effects of chronic administration of doxorubicin on myocardial creatine phosphokinase and antioxidant defenses and levels of lipid peroxidation in tissues and plasma of rats
Authors: Robison Timothy W. , Giri Shri N. , Wilson Dennis W.
Published: October 2006

Tissue and plasma levels of thiobarbituric acid reactive substances (TBARS) were measured in rats treated chronically with doxorubicin. In addition, heart creatine phosphokinase and antioxidant defenses were examined. Male rats received doxorubicin (DXR) 2 mg/kg or vehicle weekly subcutaneously for 13 weeks and were sacrificed at 14 and 19 weeks, 1 and 6 weeks after the last dose, respectively. Histological evaluation in DXR‐treated rats at 14 and 19 weeks found significant and progressive cardiac and renal lesions as compared to controls. Heart TBARS were unchanged from controls. Plasma and kidney levels of TBARS were elevated above controls at both 14 and 19 weeks. Lung levels of TBARS were significantly elevated above controls at 14 weeks. Liver levels of TBARS were elevated at 19 weeks. Heart creatine phosphokinase activity was significantly depressed from controls at both 14 and 19 weeks. Heart glutathione peroxidase and superoxide dismutase activities were unchanged from controls. Heart glutathione, glutathione reductase, glucose‐6‐phosphate dehydrogenase, and catalase were elevated above controls at both 14 and 19 weeks. The lack of change in heart TBARS suggests that changes in TBARS in other organs may be secondary processes. The depression of creatine phosphokinase suggests that levels of adenosine triphosphate may be insufficient to sustain the myocardial function and this may partly be responsible for DXR‐induced cardiac myopathy.
Adverse reactions of imidazole antifungal agents: Computer graphic studies of cytochrome P‐450 interactions
Authors: Lewis D. F. V. , Rodrigues A. D. , Ioannides C. , Parke D. V.
Published: October 2006

The imidazole antifungal agents give rise to adverse reactions and clinically relevant drug interactions. This is due to lack of specificity of the antifungal agents that interact avidly not only with the fungal but also with mammalian cytochrome P‐450 proteins. A computer graphic technique capable of predicting the interaction of these structurally‐related imidazoles with fungal and mammalian cytochrome P‐450 proteins is described. This prediction is achieved by comparing the molecular conformation of these drugs with lanosterol, the substrate of the fungal cytochrome P‐450, and with phenobarbitone, an inducing agent of a family of mammalian cytochrome P‐450, toward which the antifungal agents show highest inhibitory activity.
Niacin attenuates bleomycin‐induced lung fibrosis in the hamster
Authors: Wang Qingjian , Giri Shri N. , Hyde Dallas M. , Nakashima James M. , Javadi Iraj
Published: October 2006

Bleomycin (BLM)‐induced lung fibrosis has been shown to be accompanied by the activation of poly(ADP‐ribose) polymerase and depletion of nicotinamide adenine dinucleotide (NAD) in the lung. Niacin, a precursor of NAD, was used in the present study to investigate its possible ameliorating effect on BLM‐induced pulmonary fibrosis in hamsters. Niacin (500 mg/kg IP) or saline (IP) was injected daily for 16 or 23 days. On day 3, hamsters were treated with BLM (7.5 U/5 mL/kg) or an equivalent volume of saline intratracheally. BLM alone significantly increased lung hydroxyproline levels, bron‐choalveolar lavage fluid protein concentration, and various inflammatory cell counts in the lavage in both experiments. In addition, BLM alone elevated prolyl hydroxylase and poly(adenosine‐5′‐diphosphate [ADP]‐ribose) polymerase activities in the 3‐week study. Niacin treatment significantly decreased BLM‐elevated lung hydroxyproline, prolyl hydroxylase, and poly(ADP‐ribose) polymerase activities. Histopa‐thology revealed that niacin treatment attenuated BLM‐induced thickened alveolar septa, foci of fibrotic consolidation, and accumulations of inflammatory cells in the parenchyma and air spaces. The ability of niacin to attenuate BLM‐induced lung fibrosis in hamsters suggests that it may have potential as an antifibrotic agent in humans.
Neonatal diethylstilbestrol treatment alters aflatoxin B1‐DNA adduct concentrations in adult rats
Authors: Lamartiniere Coral A.
Published: October 2006

Aflatoxin B1‐DNA adduct concentrations were measured in the livers of adult Sprague‐Dawley CD rats treated on days 2, 4, and 6 postnatally with 1.45 μmol of diethylstilbestrol and in adulthood with phenobarbital, 3‐methylchlanthrene, or vehicle prior to treatment with aflatoxin B1. Aflatoxin B1 (1 mg/kg) was injected 5 hr prior to killing the rats. Female rats exposed neonatally to diethylstilbestrol had significantly higher aflatoxin B1‐DNA adduct concentrations (three‐ to sixfold) than adult female rats treated neonatally with propylene glycol. Liver aflatoxin B1‐DNA adduct concentrations were slightly higher in control males as compared to adduct concentrations in neonatally diethylstilbestrol‐treated males, as compared to adduct concentrations in control females (not significant [NS]). Phenobarbital and 3‐methylcholanthrene treatment followed by aflatoxin B1 injection resulted in decreased aflatoxin B1‐DNA adduct concentrations in all rats. Our results demonstrate that neonatal exposure to diethylstilbestrol alters the capacity of adult female rats to form and/or dispose of carcinogen‐DNA adducts following a single dose of aflatoxin B1 (increased adduct concentration). This alteration may be a consequence of altered imprinting mechanisms with diethylstilbestrol causing developmental modifications early in life. The animals were, however, able to respond to cytochrome P‐450 and P‐448 inducers as evidenced by decreased aflatoxin B1‐DNA adduct concentrations.
Metabolism of methacrylonitrile to cyanide: In vitro studies
Authors: Farooqui Mohammed Y. H. , Diaz Rolando G. , Cavazos Rogelio
Published: October 2006

In liver fractions from male Sprague‐Dawley rats, the metabolism of methacrylonitrile (MeAN) to cyanide (CN−) was localized in microsomal fraction and required reduced nicotinamide adenine dinucleotide phosphate (NADPH) and oxygen for maximal activity. The biotransfomation of MeAN to CN− was characterized with respect to time, microsomal protein concentration, pH, and temperature. Metabolism of MeAN was increased in microsomes obtained from phenobarbital‐treated rats (310% of control) and decreased with CoCl2 and SKF 525 A treatments (55% and 61%, respectively). Addition of the epoxide hydratase inhibitor, 1,1,1‐trichloropropane 2,3‐oxide, decreased the formation of CN− from MeAN. Addition of glutathione, cysteine, D‐penicillamine, and 2‐mercaptoethanol enhanced the released of CN− from MeAN. These findings indicate that MeAN is metabolized to CN− via a cytochrome P‐450‐dependent mixed‐function oxidase system.
Activation of benzo(a)pyrene‐7,8‐dihydrodiol in rat uterus: An in vitro study
Authors: Byczkowski Janusz Z. , Kulkarni Arun P.
Published: October 2006

Peroxidatic metabolism of benzo(a) pyrene‐7,8‐dihydrodiol by calcium containing extracts of rat uteri was investigated. Covalently bound and soluble metabolites of benzo(a)pyrene‐7,8‐dihydrodiol were quantitated by radiometry and high performance liquid chromatography, respectively

Uterine extracts incubated with benzo(a)pyrene‐7,8‐dihydrodiol activated this proximate mutagen to protein binding metabolite(s).

Hydrogen peroxide increased the protein binding and yielded a substantial amount of benzo(a)pyrene‐trans‐anti‐tetrahydrotetrol, suggesting the peroxyl‐type free‐radical epoxidation process.

The results indicate that rat uterine peroxidase is able to catalyze free‐radical activation of benzo (a)pyrene‐7,8‐dihydrodiol by epoxidation to its 9,10‐dihydrodiolepoxide, a known ultimate mutagen and carcinogen.
The effect of TCDD on Acyl CoA: Retinol acyltransferase activity and vitamin a accumulation in the kidney of male sprague‐dawley rats
Authors: Jurek Maria A. , Powers Robert H. , Gilbert Linda G. , Aust Steven D.
Published: October 2006

Previous studies have shown that rats treated with 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) show signs of toxicity that are similar to the responses of animals to a vitamin A‐deficient diet. These include hypophagia, loss of body weight, loss of hepatic vitamin A, and accumulation of renal retinoids. Male Sprague‐Dawley rats treated with 10, 30, or 100 nmol/kg of TCDD accumulated renal vitamin A, with retinyl palmitate concentrations reaching 8 times those of control animals, similar to that of male rats fed a vitamin A‐free diet for 26 days. Acyl CoA:retinol acyltransferase (ACARAT) activities in both TCDD‐treated rats and rats fed a vitamin A‐free diet for 26 days were similarly elevated, and were strongly and positively correlated with the renal retinyl palmitate concentrations. Retinol concentrations in the kidneys of rats treated with TCDD or fed a vitamin A‐free diet were only slightly elevated when compared to control rats. We suggest that accumulation of retinyl esters in the kidneys of rats treated with TCDD or fed a vitamin A‐free diet occurs as a result of increased rates of retinol esterification.
Formation of strand breaks and interstrand cross‐links in DNA by methylglyoxal
Authors: Rahman Arshad , Shahabuddin  , Hadi S. M.
Published: October 2006

Methylglyoxal (MG), a dietary mutagen, is present in various frequently consumed beverages and foods and in cigarette smoke. A combination of S1 nuclease hydrolysis and alkaline unwinding assay was used to demonstrate the formation of single‐strand breaks and interstrand cross‐links in DNA upon treatment with MG. Calf thymus DNA, when treated with increasing concentrations of MG, showed an increasing degree of S1 nuclease hydrolysis. It also showed the formation of an increasing number of strand breaks per molecule as determined by an alkaline unwinding assay. Incubation of DNA with relatively higher concentrations of methylglyoxal or prolonged treatment gave increased thermal melting temperatures and an enhanced rate of reannealing after thermal denaturation. These results indicated the formation of interstrand cross‐links. Upon treatment with MG, A‐T base pair depleted DNA showed a reduced number of single‐strand break formation. It also showed a significantly lower decrease in Tm as compared with MG‐treated normal DNA. These results showed that under the conditions used, MG primarily reacts with A‐T base pairs in duplex DNA.