bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of carbon tetrachloride‐induced lipid peroxidation by novel antioxidants in rat hepatic microsomes: Dissociation from hepatoprotective effects in vivo
Authors: Wolfgang G. H. I. , Jolly R. A. , Donarski W. J. , Ochoa R. , Petry T. W. 
Published: October 2006

AbstractThe ability of two novel antioxidants, U‐74,006F and U‐78,517G, as well as the known antioxidant N,N′‐diphenyl‐p‐phenylenediamine to inhibit lipid peroxidation induced by carbon tetrachloride (CCl4) was investigated in Aroclor 1254‐induced rat hepatic microsomes. All three compounds completely inhibited lipid peroxidation in microsomes as measured by the formation of thiobarbituric acid reactive substances (TBARS). Inhibition of lipid peroxidation was not a function of decreased bioactivation of CCl4, as the compounds did not substantially inhibit benzphetamine N‐demethylase activity or covalent binding of [14‐C]CCl4 to lipid or protein. Parallel studies examined the hepatoprotective effects of the compounds in vivo. Rats were pretreated with antioxidant or vehicle prior to administration of CCl4 (300 or 600 μL/kg i.p.). Sera were collected 24 h postadministration of CCl4 and analyzed for alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities and total bilirubin. Administration of CCl4 produced elevations in ALT, moderate changes in bilirubin, and no change in ALP activities. Histological examination of CCl4‐treated livers revealed lipidosis and centrilobular necrosis. The antioxidants partially improved the clinical chemistry parameters, but had minimal effects on the histological lesion. In contrast to the complete inhibition of lipid peroxidation observed in the in vitro studies, none of the antioxidants markedly protected against CCl4‐induced toxicity in vivo.
In vivo toxicity and pulmonary effects of promazine and chlorpromazine in rats
Authors: Kodavanti Urmila P. , Lockard Virginia G. , Mehendale Harihara M. 
Published: October 2006

AbstractCationic amphiphilic drugs induce a phospholipid storage disorder known as phospho‐lipidosis. Halogenated analogs of the drugs are more potent inducers of phospholipidosis when compared to nonhalogenated analogs. Two such antipsychotic drugs, promazine and chlorpromazine, are effectively taken up by the lungs and induce lamellar inclusions in vitro. We compared the in vivo toxicity and efficacy of promazine and chlorpromazine to induce phospholipidosis in the lung and in pulmonary alveolar macrophages. Male Sprague‐Dawley rats were given promazine or chlorpromazine (25 mg/kg/day, P.O., in water) for 5 weeks. Food intake was decreased in promazine‐ and chlorpromazine‐treated rats, chlorpromazine rats being affected more than promazine rats. To minimize experimental error due to starvation, control rats were pair‐fed. The body weight gain was decreased in chlorpromazine rats in comparison to pair‐fed controls. Chlorpromazine‐treated rats, but not promazine‐treated rats, showed increased mortality over the 5‐week treatment period. Histopathologic examination of lung revealed loss of alveolar macrophages with no other gross abnormalities in chlorpromazine‐treated rats. Quantitative analysis of lung lavage also showed significant reduction in the number of macrophages. This finding is in contrast to other cationic amphiphilic drugs, which induce phospholipidosis as well as accumulation of alveolar macrophages. Phospholipid level increased in alveolar macrophages but not in lavaged lung following chlorpromazine treatment. Acid phos‐phatase activity in lavaged lung homogenate and macrophages of promazine‐ and chlorpromazine‐treated rats,taken as an index of toxicity to cells, did not differ significantly from control rats. In vivo binding of promazine and chlorpromazine to the lamellar bodies isolated from lungs was quantitated using 1,6‐diphenyl‐1,3,5‐hexatriene and 1‐anilino‐8‐naphthalene sulfonate as fluorescence probes for hydrophobic and hydrophilic moieties, respectively. 1,6‐Diphenyl‐1,3,5‐hexatriene or 1‐anilino‐8‐naph‐thalene sulfonate fluorescence with lamellar bodies did not differ in control, promazine‐, or chlorpromazine‐treated rats, indicating that sufficient drug was not bound to lamellar bodies to be sensitive enough to detect using fluorescence probes. Thin‐layer chro‐matography identification of these drugs from lung extract revealed no detectable spots against the authentic drug standards indicating that promazine and chlorpromazine may not accumulate significantly in the lung in vivo to be detected by thin‐layer chromatography. These results indicate that chlorpromazine is more toxic to rats than promazine and decreases the alveolar macrophages, suggesting that macrophages are the targets of chlorpromazine‐in‐duced phospholipidosis. Long‐term chlorpromazine and promazine treatment may lead to phospholipidosis in alveolar macrophages, which can be a sensitive indicator of this disorder.
Sublethal effects of pentachlorophenol in the abalone (haliotis rufescens) as measured by in vivo 31P NMRSpectroscopy
Authors: Tjeerdema Ronald S. , Fan Teresa W.‐M. , Higashi Richard M. , Crosby Donald G. 
Published: October 2006

AbstractThe sublethal biochemical effects of pentachlorophenol (PCP) were investigated in live, intact red abalones (Haliotis rufescens), using a flow‐through exposure system, by in vivo 31P NMR spectroscopy. Based on rangefinding tests (6‐hr LC50 = 1.6 mg/L; 6‐hr no‐observable‐effect‐level (NOEL) = 0.8 mg/L), three abalones were separately exposed to a sublethal concentration (1.2 mg/L) for 5 hr, followed by a 13 hr recovery period. Effects in foot muscle included both a decrease in phosphoarginine and an increase in inorganic monophosphate concentrations ([PA] and [Pi], respectively); both foot muscle concentrations of adenosine triphosphate [ATP] and intracellular pH (pHi) also declined. Parallel in vitro experiments revealed that concentrations of glycerol 3‐phosphate, lactate, citrate, succinate, malate, and alanine (Ala) all increased, while those of glyceraldehyde 3‐phosphate and glutamine (Gln) remained stable. Also, these effects were not evident until 2 hr into exposure, possibly the time required for PCP to attain an effective concentration in foot muscle. During recovery, while Pi declined to pre‐exposure levels, [PA] completely recovered in only one individual. Also, realkalinization of pHi was similar to recovery of [Pi], and ATP returned to near‐initial levels, as did glycerol 3‐phosphate, lactate, succinate, malate, and Ala; glyceraldehyde 3‐phosphate, citrate, and Gln levels declined. Recovery responses corresponded to the time for PCP clearance from foot muscle. The effects of PCP were similar to those of hypoxia, fatigue, hypersalinity, and arginine kinase inhibitors, and so sublethal PCP concentrations may also inhibit electron transport and arginine kinase as well as uncouple mitochondrial oxidative phosphorylation in intact molluscs. Thus, the effects of pollutants on key biochemical processes may now be measured in intact aquatic organisms as they occur, improving our ability to accurately assess the environmental effects of pollutants in the laboratory.
Effects of inhibition of cystathionase activity on glutathione and metallothionein levels in the adult rat
Authors: Houghton Caroline B. , Cherian M. George 
Published: October 2006

AbstractThe effects of alterations in sulfur metabolism on hepatic and renal metallothionein and glutathione metabolism were studied in the adult rat using inhibition of two enzymes of these pathways, hepatic cystathionase and renal gamma‐glutamyl transpeptidase. Rats were fed a diet containing both methionine (0.66%) and cystine (0.20%) for 1 week before receiving three consecutive daily intraperitoneal injections of propargylglycine, a selective cystathionase inhibitor, at various doses (2.5–375 μmol/kg). When hepatic cystathionase was inhibited greater than 90% (≥50 μmol propargylglycine/kg), renal and hepatic metallothionein and hepatic glutathione were unaltered except at the highest dose. On the other hand, renal glutathione was increased twofold with a concomitant decrease in renal gamma‐glutamyl transpeptidase activity (50% of control). In another experiment, when renal gamma‐glutamyl transpeptidase was inhibited greater than 90% with three consecutive daily injections of acivicin, a selective gamma‐glutamyl transpeptidase inhibitor (10 mg/kg IP), renal glutathione content was unaltered while hepatic glutathione was decreased. Renal and hepatic metallothionein were not changed. Thus, the cysteine pools for metallothionein and glutathione appear unrelated under the present experimental conditions. In addition, following either propargylglycine or acivicin injections, renal and hepatic glutathione pools appear to be altered differently. These results suggest that renal glutathione may be preferentially maintained even when hepatic glutathione is decreased.
Activation of γ‐aminobutyric acid insensitive chloride channels in mouse brain synaptic vesicles by avermectin B1a
Authors: Payne Gregory T. , Soderlund David M. 
Published: October 2006

AbstractThe interaction of avermectin B1a (AVMB1a) with mouse brain chloride channels was characterized using a radiochloride efflux assay. The loss of intravesicular chloride from synaptoneurosomes preloaded with 36Cl involved an initial rapid phase followed by a slower phase that approached equilibrium within 10 min. AVMB1a stimulated a 30% loss of intravesicular chloride within the first 2 s of exposure; however, AVMB1a had no effect on the rate of the slower phase of chloride loss. Experiments with lysed synaptoneurosomes showed that both chloride loading and basal and AVMB1a‐stimulated chloride release required the presence of intact vesicles. The efflux of 36Cl from mouse brain synaptosomes and the stimulation of efflux by AVMB1a were qualitatively similar to the results obtained with synaptoneurosomes but involved much lower overall levels of chloride loading and release. AVMB1a produced halfmaximal stimulation of chloride efflux from synaptoneurosomes at a concentration of 2.1 ± 0.3 μM and a 35.4 ± 1.4% maximal loss of intravesicular chloride at saturating concentrations. γ‐Aminobutyric acid (GABA), bicuculline, or the chloride channel blockers picrotoxinin, t‐butylbicyclophosphorothionate (TBPS) 4,4′‐diisothiocyanatostilbene‐2,2′‐disulfonic acid (DIDS), and anthracene 9‐carboxylic acid (9‐CA) had little or no effect on the loss of chloride from synaptoneurosomes either in the presence or the absence of AVMB1a. However, the chlorinated cycloalkane insecticides dieldrin and lindane were equally effective as inhibitors of GABA‐dependent chloride uptake and AVMB1a‐stimulated chloride efflux. These data demonstrate that AVMB1a‐stimulated chloride efflux from mouse brain synaptic vesicles results from the activation of GABA‐insensitive chloride channels and that this action is distinct from their previously documented effects on GABA‐gated chloride channels in mouse brain preparations. Our findings imply that both GABA‐gated and GABA‐insensitive chloride channels may be toxicologically significant targets for the action of avermectins.
Species differences in ciprofibrate induction of hepatic cytochrome p450 4A1 and peroxisome proliferation
Authors: Makowska Janet M. , Gibson G. Gordon , Banner Frank W. 
Published: October 2006

AbstractSix species (CD‐1 mouse, Fischer 344 rat, Syrian golden hamster, Duncan‐Hartley guinea pig, half‐lop rabbit and marmoset monkey) were treated orally with ciprofibrate, a potent oxyisobutyrate hypolipidaemic drug for 14 days. A dosedependent liver enlargement was observed in the mouse and rat and at the high dose level in the hamster. A marked dose‐dependent increase in the 12‐hydroxylation of lauric acid was observed in the treated mouse, hamster, rat, and rabbit, associated with a concomitant elevation in the specific content of cytochrome P‐450 4A1 apoprotein, determined by an ELISA technique. Similarly, in these responsive species, an increase in mRNA levels coding for cytochrome P450 4A1 was observed. Lauric acid 12‐hydroxylation was unchanged in the guinea pig and marmoset after ciprofibrate pre‐treatment, and cytochrome P‐450 4A1 was not detected immunochemically in liver microsomes from these latter species. In the untreated mouse, hamster, rat, and rabbit, the 12‐hydroxylation of lauric acid was more extensive than the 11‐hydroxylation, whereas in the guinea pig and marmoset the activity ratios were reversed, with 11‐hydroxylation predominating. Peroxisomal fatty acid β‐oxidation was markedly induced in the mouse, hamster, rat, and rabbit on treatment at the higher dose level (39‐, 3‐, 13‐ and 5‐fold, respectively) and was slightly increased in the marmoset (2‐fold), yet was unchanged in the guinea pig following treatment. In the marmoset the increase in peroxisomal β‐oxidation was 3‐ to 4‐fold at the high dose level; however, the dose levels used in the marmoset were 20 and 100 mg/kg as opposed to 2 and 20 mg/kg in the other species. The differences in the foregoing hepatic enzyme responses to ciprofibrate between the species examined in our studies indicate a specific pattern of enzyme changes in responsive species. In the responsive species (rat, mouse, hamster, and rabbit), cytochrome P‐450 4A1 specific content and related enzyme activity were increased concomitant with elevated peroxisomal β‐oxidation. By contrast, the marmoset and guinea pig lack the coordinate hepatic induction of peroxisomal and microsomal parameters and may be categorized as less responsive species. Accordingly, the rat hepatic responses to peroxisome proliferators cannot confidently be used to predict biological responses in primates, with obvious implications for the extrapolation of animal data to man.
Influence of single and concurrent clofibrate and phenobarbital administration on cytochrome P450‐dependent mixed function oxidase activities and peroxisome proliferation in male rat liver
Authors: Close Ian , Shackleton Gareth , Goldfarb Peter S. , Gibson G. Gordon , Sharma Raj , Howes Doug 
Published: October 2006

AbstractThe influence of both single and concurrent administration of phenobarbital and clofibrate on hepatomegaly, cytochrome P450‐depen‐dent mixed function oxidase activities, and peroxisome proliferation in male rat liver have been studied. Both xenobiotics separately increase the liver :body weight ratio and their combined administration results in greater hepatomegaly than either compound alone. Both compounds induce NADPH‐cytochrome c(P450) reductase activity and laurate ω‐ and ω‐1‐hydroxylase activities, but only phenobarbital induces pentoxyresorufin‐O‐de‐alkylase. None of the drug treatments induced microsomal cytochrome b5. Phenobarbital did not cause peroxisome proliferation and inhibited the corresponding clofibrate‐dependent proliferation. Taken collectively, our studies have demonstrated that concomitant treatment with phenobarbital and clofibrate are largely permissive with respect to the hepatic mixed function oxidase system but have opposing effects on the phenomenon of peroxisome proliferation in the same tissue.
Perfluorooctanoic acid has persistent effects on peroxisome proliferation and related parameters in mouse liver
Authors: Sohlenius Anna‐Karin , Lundgren Bo , DePierre Joseph W. 
Published: October 2006

AbstractMale C57B1/6 mice were treated for 5 days with 0.05% perfluorooctanoic acid (PFOA) in their diet. This treatment resulted in a potent induction of peroxisomal fatty acid β‐oxidation in the liver. In order to investigate recovery from treatment with PFOA, mice were given normal laboratory chow for up to 20 days after termination of PFOA administration. It was established that the activities of peroxisomal lauoryl‐CoA oxidase and palmitoyl‐CoA oxidation were still elevated 2–3 weeks after termination of treatment. The catalase activity recovered in the cytosolic fraction was also still significantly elevated after 20 days with normal laboratory chow. Furthermore, the protein content of the mitochondrial fraction was increased by PFOA and had not returned to control level at the end of the recovery period. Perfluorooctanoic acid also caused a persistent effect in omega hydroxylation of lauric acid (cytochrome P‐452). The activities of cytosolic DT‐diaphoreses and glutathione transferase were also enhanced by PFOA. However, these two enzymes recovered relatively rapidly from the treatment (2–20 days). This study reveals two different patterns of recovery from PFOA treatment, one involving parameters that recovered completely, or almost completely, from PFOA treatment after 20 days and another involving parameters that were still elevated at the end of the recovery period.
Studies on the interaction of furan with hepatic cytochrome P‐450
Authors: Parmar Devendra , Burka Leo T. 
Published: October 2006

AbstractIn vitro incubation of rat liver micro‐somes with [14C]‐furan in the presence of NADPH resulted in the covalent incorporation of furan‐derived radioactivity in microsomal protein. Compared to microsomes from untreated rats a two‐ to threefold increase in binding was observed with microsomes from phenobarbital‐treated rats and a four‐ to five‐fold increase was observed with microsomes from rats pretreated with imidazole or pyrazole. Covalent binding was reduced with microsomes from rats pretreated with β‐naphthoflavone. Chemicals containing an amine group (semicarbazide), those in which the amine group is blocked but have a free thiol group (N‐acetylcysteine), and those which have both an amine and a thiol group (glutathione) effectively blocked binding of [14C]‐furan to microsomal protein. A decrease in cytochrome P‐450 (P‐450) content and decreases in the activities of P‐450‐dependent aniline hydroxylase, 7‐ethoxycoumarin‐O‐deethylase (BCD), and 7‐ethoxyresorufin‐O‐deethylase (ERD) was observed 24 hours after a single oral administration of 8 or 25 mg/kg of furan, suggesting that the reactive intermediate formed during P‐450 catalyzed metabolism could be binding with nucleophilic groups within the P‐450. In vitro studies indicated a significant decrease in the activity of aniline hydroxylase in pyrazole microsomes and BCD in phenobarbital microsomes without any significant change in the CO‐binding spectrum of P‐450 or in the total microsomal heme content, suggesting that furan inhibits the P‐450s induced by PB and pyrazole. An almost equal distribution of furan‐derived radioactivity in the heme and protein fractions of the CO‐binding particles after In vitro treatment of microsomes with furan suggests binding of furan metabolites with heme and apoprotein of P‐450, and, probably, due to this interaction, furan is acting as a suicide inhibitor of P‐450.
The role of metals in the enzymatic and nonenzymatic oxidation of epinephrine
Authors: Ryan Timothy P. , Miller Dennis M. , Aust Steven D. 
Published: October 2006

AbstractThe effects of transition metals on nonenzymatic and ceruloplasmin catalyzed epinephrine oxidation were investigated by studying rates of epinephrine oxidation in purified buffers and in the presence of metal chelating agents. We found that epinephrine does not “autoxidize” in sodium chloride solutions prepared with deionized water that was further purified by chromatography over Chelex 100 resin prior to use. Epinephrine was oxidized rapidly in sodium chloride prepared with tap water (1.20±0.12 nmoles/min) or in deionized water (0.40±0.80 nmoles/min), but this oxidation was prevented by the addition of Desferal, a potent metal chelating agent. Epinephrine oxidation was enhanced upon the addition of ceruloplasmin, and this oxidation rate could be slowed, but not eliminated, by the addition of Desferal. If epinephrine solutions were preincubated for 72 hours with Desferal prior to ceruloplasmin addition, however, no oxidation was observed. Epinephrine was shown to form colored complexes with both iron and copper at pH 7.0. The Fe(III)‐epinephrine complex was much more stable than was the Cu(II)‐epinephrine complex. Oxygen consumption studies of ceruloplasmin catalyzed epinephrine oxidation showed that copper was a better promoter of epinephrine oxidation than was iron, suggesting that ceruloplasmin‐catalyzed epinephrine oxidation results from adventitious copper bound to the purified enzyme. In light of these results, the physiological relevance of ceruloplasmin catalyzed oxidation of biogenic amines may be minor.
2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) alters pancreatic membrane tyrosine phosphorylation following acute treatment
Authors: Ebner Karl , Enan Fumio Matsumura Essam , Olsen Hugh 
Published: October 2006

AbstractTo understand the basic mechanisms of TCDD's action to cause hypoinsulinemia in several experimental animals, we have studied TCDD‐induced changes in various protein kinase activities in membrane preparations of guinea pig pancreas. For this purpose, young male guinea pigs were treated through a single intraperitoneal in jection with 1 or 3 μg/kg of TCDD in vivo, and, after given time periods, pancreas samples were obtained and membranes were isolated through homogenization and centrifugation procedures. Several sets of incubation conditions were selected for protein kinase activity assay, each favoring a specific type of protein kinase. It was found that overall protein phosphorylation activities were higher in the preparation from TCDD‐treated an imals as compared to those found in pair‐fed controls and that this trend was more pronounced when the assay medium contained Mn2+ in place of Mg2+ and EGTA. These are the conditions that are known to favor protein tyrosine kinases. Other types of protein kinases from the treated animals did not show any significant differences from the pair‐fed control animals, though that of protein kinase C in the treated preparation showed a modest increase. To establish that the type of protein kin ases stimulated by TCDD are protein tyrosine kin ases, we have carried out phosphoamino acid analyses, KOH digestion, and western blot analyses using an antibody to phosphotyrosine. All the results were consistent in supporting the idea that TCDD causes a rise in protein‐tyrosine kinases in pancreas at early stages of poisoning.
Toxicokinetics and biotransformation of pentachlorophenol in the topsmelt (Atherinops affinis)
Authors: Benner Diana B. , Tjeerdema Ronald S. 
Published: October 2006

AbstractThe toxicokinetics and biotransformation of pentachlorophenol (PCP) were determined in the topsmelt (Atherinops affinis) In a static system, topsmelt (n = 9) were exposed to 50 μg/L of [U‐14C]PCP for 24 hours to determine the absorption rate constant (Ka), the whole‐body bio‐concentration (at steady‐state conditions), the elimination rate constant UQ, and the elimination half‐life (t1/2). Kinetics were determined by direct quantitation of radioactivity in the exposure water. Following exposure, fish were placed in a flow‐through metabolism chamber for 24 hours to allow depuration of retained residues, which were collected on XAD‐4 resin. Excreted residues were identified and quantified by high‐pressure liquid co‐chromatography, fraction collection, and liquid scintillation counting. The Ka and Ke, calculated using a simplified model, were 0.012 M‐1 0.005/h and 0.014±;0.003/h, respectively, while the 24 hour total concentration factor was 278.0×182.0 and the t1/2 was 52.7±;11.2. During 24 hours of exposure to dean seawater, topsmelt depurated 32.9% of retained residues, and while PCP was primarily excreted unchanged (64.9%), significant amounts of both pentachlorophenylsulfate (18.9%) and pentachloro‐β‐D‐glucuronide (16.2%) were also formed.