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Biomedical subjects

W J Murray

Publications and source records attributed to W J Murray.

At least 19 recordsLinked to original sources
PubMed1990

Desferrioxamine-induced alterations in hepatic iron distribution, DNA damage and lipid peroxidation in control and 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats.

Desferrioxamine (DFX), an iron chelator, has been used to inhibit in vitro redox cycling of the transition iron irons that may interfere with free-radical formation, and is used clinically to treat conditions associated with iron overload. The effect of DFX on hepatic iron distribution has not been examined. Therefore, we have examined the effect of DFX on iron content and distribution, lipid peroxidation and DNA single-strand breaks in liver. Since 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) enhances hepatic lipid peroxidation and induces DNA damage, the ability of DFX to modulate these effects was also examined. Female Sprague-Dawley rats received 200 mg DFX kg-1 i.p. every 12 h for 10 days and 50 micrograms TCDD kg-1 p.o. on Day 4 as a single dose. All animals were killed 7 days after TCDD administration. The results demonstrate that DFX alone did not decrease hepatic iron content, but enhanced the iron distribution in mitochondria, microsomes and nuclei. A 10-day administration of DFX resulted in enhanced hepatic lipid peroxidation and DNA single-strand breaks, consistent with the alterations in iron distribution. TCDD administration produced large increases in lipid peroxidation in microsomes, nuclei and whole-liver homogenates, as well as enhanced DNA damage. However, the marked increases in lipid peroxidation produced by TCDD were attenuated by DFX, while the DNA damaging effects of TCDD and DFX were additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Hepatic lipid peroxidation, sulfhydryl status, and toxicity of the blue-green algal toxin microcystin-LR in mice.

Microcystin-LR (MCLR), a cyclic heptapeptide produced by the blue-green algae Microcystis aeruginosa, produces death in female mice treated with 100 micrograms MCLR/kg. Kupffer-cell hyperplasia was observed histologically after treatment with 50 or 100 micrograms MCLR/kg. No other changes or lethality were observed with the 50 micrograms MCLR/kg, while 100% lethality occurred in less than 2 h in mice treated with 100 micrograms/kg. In these animals liver weights increased by 45% and hepatic hemoglobin content increased 106% at 60 min posttreatment. Liver histology showed loss of hepatic architecture and necrosis 30 min after treatment, and congestion with blood became evident at 45 min after treatment. Serum enzymes were significantly increased 45 min posttreatment. Hepatic nonprotein sulfhydryl content decreased 19% when calculated on the basis of cytosolic protein and 39% when based upon the total protein content, respectively. The sulfhydryl content of the liver cytoskeletal fraction decreased 26% by 30 min after treatment. Decreased enzyme-mediated and increased non-enzyme-mediated lipid peroxidation were observed in hepatic microsomes following both in vivo and in vitro exposure of hepatic microsomes to MCLR. The toxicity of MCLR may be related to alterations in the sulfhydryl content of the cytoskeletal protein. Furthermore, MCLR may either directly or indirectly affect microsomes, suggesting alterations in structure and function of smooth endoplasmic reticulum.

Alanine Transaminase↗
PubMed1990

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced decrease in the fluidity of rat liver membranes.

1. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCCD)-induced lipid peroxidation has previously been demonstrated by assessing the hepatic content of thiobarbituric acid reactive substances (TBARS) as well as the NADPH-dependent microsomal formation of TBARS as well as the NADPH-dependent microsomal formation of TBARS using malondialdehyde as the standard. 2. Changes in membrane fluidity as a result of lipid peroxidation may occur. Therefore the dose- and time-dependent effects of TCDD on lipid peroxidation in mitochondrial, microsomal, and plasma membranes, and changes in membrane fluidity in these subcellular fractions, were examined. Animals were treated with either 50 or 100 micrograms TCDD/kg orally, and killed 3, 6, or 9 days post-treatment. 3. Time-dependent increases occurred in TBARS content and formation following TCDD administration for all three membranes. Similar results were observed after 50 and 100 micrograms TCDD/kg. 4. Following TCDD administration, fluorescence polarization measurements as determined by the fluorescence polarization (r) and anisotropy parameter (a.p.) values demonstrated significant decreases in membrane fluidity in all membrane fractions, indicative of membrane structural alterations. 5. Excellent inverse correlations between lipid peroxidation and membrane fluidity were observed. Thus, decreased membrane fluidity and increased membrane damage may contribute to the toxic manifestations of TCDD as a consequence of an oxidative stress.

Animals↗
PubMed1989

Comparative effects of pair-feeding and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on various biochemical parameters in female rats.

Hypophagia is a common characteristic of the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and may be responsible for some of the toxic manifestations. Pair-feeding has been used in control animals to compensate for the hypophagia, but relatively few studies have assessed biochemical changes associated with pair-feeding versus weight loss induced by TCDD. Rats were treated with TCDD and killed 7 days post-treatment while pair-fed animals received an amount of diet equivalent to TCDD-treated partner animals. Ad libitum-fed rats were also used. No correlations were seen in altered calcium and iron homeostasis between pair-feeding and TCDD administration relative to ad libitum-fed animals. Pair-feeding resulted in greater alterations than TCDD administration in the subcellular distribution of iron in mitochondria, microsomes and cytosol. Pair-feeding also resulted in greater accumulation of calcium in mitochondria and microsomes in pair-fed as compared to TCDD-treated animals. Greater lipid peroxidation was observed in whole liver and nuclei of rats receiving TCDD relative to pair-fed animals. A significantly greater incidence of DNA single strand breaks occurred in hepatic nuclei of TCDD-treated animals as compared to pair-fed and ad libitum-fed animals. Significantly greater inhibition of hepatic glutathione peroxidase activity and thymic involution were observed in TCDD treated animals as compared to the pair-fed group. Although some similarities existed between TCDD-treated animals and pair-fed rats, the overall biochemical changes which were observed following TCDD administration cannot be attributed to weight loss associated with hypophagia.

Animals↗
PubMed1989

Factors influencing the induction of DNA single strand breaks in rats by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

The ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to induce lipid peroxidation and DNA damage in rat hepatic nuclei was investigated. In addition, the role of iron in hepatic DNA damage was examined. Female Sprague-Dawley rats were treated with a single dose of 25--100 micrograms TCDD/kg orally, and sacrificed 3-14 days after treatment. Liver nuclei were isolated, and DNA single strand breaks (DNA-SSB) and lipid peroxidation were determined. Lipid peroxidation was assessed by measuring the content and production of thiobarbituric acid reactive substances (TBARS) while DNA-SSB were determined by the alkaline elution technique. The results demonstrate that TCDD dose and time-dependent increases in hepatic nuclear TBARS content and production occur in conjunction with an increase in DNA-SSB. The administration of the dithiolthione antioxidant oltipraz (30 mg/kg/day for 10 days) resulted in a significant decrease (47%) in the incidence of TCDD-induced DNA-SSB. Clofibrate administration (100 mg/kg/day for 12 days) and pair feeding had no effect on TCDD-induced DNA-SSB. The incubation of hepatic microsomes and mitochondria from TCDD-treated rats with nuclei from untreated animals for one hr at 37 degrees C resulted in enhanced DNA damage which was abolished by the addition of 0.10 mM desferrioxamine (DFX). Incubation with cytosol had no significant effect. Incubation of 0.10 mM Fe2+ or Fe3+ with isolated hepatic nuclei from untreated rats produced significant increases in DNA-SSB, which were abolished by the addition of 0.10 mM DFX to the incubation medium. TCDD may produce an increased bioavailability of iron which leads to enhanced DNA single strand breaks and lipid peroxidation in hepatic nuclei.

Animals↗
PubMed1989

Radiolabeled 9- or 10-monoiodostearic acid and 9- or 10-monoiodostearyl carnitine--I. Synthesis and purification.

The purpose of this investigation was to synthesize and purify radiolabeled 9- or 10-monoiodostearyl carnitine for potential use as a perfusion and metabolic imaging agent for the heart. Oleic acid was iodinated via a free radical addition reaction of HI across the double bond to give 9- or 10-monoiodostearic acid which in turn was esterified with carnitine. The identity of 9- or 10-monoiodostearic acid and 9- or 10-monoiodostearyl carnitine was determined using nuclear magnetic resonance (NMR), infrared (i.r.), ultraviolet (u.v.), and mass spectroscopy. The purity of the fatty acid and carnitine ester was established by thin layer chromatography. 9- or 10-Monoiodo[125I]stearic acid and 9- or 10-monoiodo[125I]stearyl carnitine were synthesized via the isotopic exchange of 125I for cold iodine bonded to 9- or 10-monoiodostearic acid and 9- or 10-monoiodostearyl carnitine.

Carnitine↗
PubMed1988

Biochemical and functional effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the heart of female rats.

Biochemical, functional and morphologic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the hearts of female rats were examined. Six days after the treatment of rats with TCDD, the blood pressures and resting heart rates were significantly less than in control animals. Treated animals were also less responsive to the effects of the beta-1 agonist, (-)isoproterenol. No histopathologic changes were observed in the heart although extensive centrilobular necrosis occurred in the liver after TCDD administration. Serum levels of thyroxine were 66% less than in control animals. Marked lipid peroxidation was produced in the liver with small but significant increases occurring in the heart. TCDD administration had no effect on catalase activity in the heart, but produced a 20% decrease in superoxide dismutase activity relative to control animals. The effects of TCDD on cardiac function do not appear to be due to a direct action of the xenobiotic on the heart but possibly to a down-regulation of beta-receptors in the heart as a result of the hypothyroid state.

Animals↗
PubMed1988

Double-blind comparison of nalbuphine and meperidine in combination with diazepam for intravenous conscious sedation in oral surgery outpatients.

Nalbuphine and meperidine were compared as analgesic components of intravenous conscious sedation in a double-blind, prospective trial of 47 patients undergoing elective oral surgery. Subjects were evaluated for pain intensity, pain relief, anxiety, sedation, recall, and vital signs at systematic observation points intraoperatively and postoperatively. At the conclusion of surgery 83% of patients who had received nalbuphine and 86% of patients treated with meperidine indicated complete pain relief. One observed adverse reaction was attributed to meperidine and another to the sedative component diazepam. No statistically significant differences were observed between nalbuphine and meperidine treatments.

Adult↗
PubMed1988

Comparison of nalbuphine and fentanyl in combination with diazepam for outpatient oral surgery.

Nalbuphine and fentanyl were compared as analgesic components of intravenous conscious sedation with diazepam in a double-blind, prospective trial of 50 patients undergoing elective oral surgery. Subjects were evaluated for intensity of pain, pain relief, sedation, anxiety, recall, and vital signs at systematic observation points intraoperatively and postoperatively. At the conclusion of surgery, 88% who received nalbuphine and 87% treated with fentanyl indicated complete pain relief. One observed adverse reaction was attributed to the combination of fentanyl and the sedative component diazepam. No statistically significant differences were observed between nalbuphine and fentanyl treatments.

Adult↗
PubMed1988

Searching for the endogenous benzodiazepine using the graph theoretical approach.

The graph theoretical indices of several compounds with reported benzodiazepine receptor binding affinities were calculated. Our results demonstrate a structural similarity among diazepam, triazolam, and the beta-carboline nucleus and a structural dissimilarity to the purines and nicotinamide. This result correlates with their respective binding affinities. Using the graph theoretical indices as structural descriptors of the benzodiazepines and the significant ligands of the beta-carbolines, a search for peptide sequences as potential ligands was explored. Single amino acids through pentapeptides with all possible amino acid substitutions and chemical modifications were calculated. The peptides generated were subjected to graph theoretical analysis, and their indices were compared to those of the benzodiazepines. Comparisons resulted in seven dipeptides and six tripeptides that are topologically similar to the benzodiazepines and beta-carbolines. The dipeptides are histidine- or tryptophan-containing compounds with pyroglutamine, phenylalanine, and tyrosine residues in the second position. The tripeptides have two aromatic amino acid residues and a pyroglutamine or glycyl terminal residue. These structures are promising candidates because (1) they are structurally (topologically) similar to the benzodiazepines, represented by diazepam and triazolam, and to the beta-carbolines; and (2) they are sequences that may reasonably form a part of a larger peptide or that may be formed metabolically by proteolysis.

Anti-Anxiety Agents↗
PubMed1988

Quantitative structure-activity study on human pharmacokinetic parameters of benzodiazepines using the graph theoretical approach.

The graph theoretical indices for a series of 13 benzodiazepines were calculated using a graph-path topological method. The total molecule, the ring fragments, and combinations of ring fragments were subjected to a quantitative structure-activity analysis using eight pharmacokinetic parameters. The metabolic clearance and the blood-to-plasma concentration ratios were most highly correlated with the graph theoretical indices, with R values of 0.975 and 0.938, respectively. These correlations were found when the diazepine + benzo fragment and phenyl fragment were used to calculate the graph-path indices. Terminal disposition half-life was correlated with the benzo + diazepine fragment, with R = 0.969. Truncating the graph-path codes by eliminating cycles in the total molecule markedly improved the correlation coefficients. When compared to the graph-path indices for the total molecule, the correlation coefficients for the terminal disposition half-life and metabolic clearance data rose from 0.721 to 0.935 and from 0.770 to 0.968, respectively, using the graph-path indices of the truncated molecule. Intrinsic clearance of unbound drug also was poorly correlated with the total molecule (r less than 0.7) but rose significantly using the graph-path indices of the truncated molecule (r = 0.971 and 0.975 for the well-stirred and parallel-tube models, respectively).

Anti-Anxiety Agents↗
PubMed1988

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induced perturbation of calcium distribution in the rat.

Altered calcium homeostasis may play a central role in the liver injury produced by some toxicants. Therefore, the dose and time dependent effects of TCDD on calcium distribution in whole homogenate and subcellular fractions of liver were examined. Groups of female rats were treated with 40 micrograms TCDD/kg for 1, 2 or 3 days. Animals treated with TCDD for 1 and 2 days were killed 1 day after treatment. Rats treated for 3 days were killed on days 1, 3, 5, 7, 9 and 12 post-treatment. A 2-fold increase in calcium content in whole homogenate occurred 5 days post-treatment. Increases in mitochondrial calcium were noted 3 days post-treatment, and significant increases in microsomal calcium were observed one day post-treatment. Small increases in cytosolic calcium also occurred. Thus, TCDD produces disturbances in the content and subcellular distribution of calcium which may contribute to the promotion of toxic manifestations by this xenobiotic.

Animals↗