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Biomedical subjects

L J King

Publications and source records attributed to L J King.

At least 19 recordsLinked to original sources
PubMed1995

Synthesis and evaluation of pharmacological and pharmacokinetic properties of monopropyl analogs of 5-, 7-, and 8-[[(trifluoromethyl)sulfonyl]oxy]-2-aminotetralins: central dopamine and serotonin receptor activity.

In order to explore further the structure-activity relationships of serotonergic and dopaminergic ligands, a series of enantiopure 5-, 7-, or 8-triflate (-OTf)-substituted 2-(monopropylamino)-tetralins have been synthesized and evaluated in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, the 8-OTf-substituted compound R-(+)-6 was found to be a potent and selective 5-HT1A (5-hydroxytryptamine) receptor agonist inducing a full-blown 5-HT syndrome in normal rats, while the corresponding 5-OTf-substituted compound S-(-)-12 was found to be a preferential dopamine (DA) autoreceptor agonist. A partial 5-HT syndrome was also observed for S-(-)-12, while the corresponding R-(+)-12 was found to be inactive at the DA and 5-HT receptors both in vitro and in vivo. Compounds 6 and 12 were found to be major urinary metabolites following oral administration of their dipropyl analogs (2 and 13, respectively). Thus 6 was proposed to be the metabolite responsible for the full-blown 5-HT syndrome seen after oral (but not subcutaneous) administration of 2. Similarly, 12 was proposed to be the metabolite responsible for the partial 5-HT syndrome seen after oral (but not subcutaneous) administration of 13. The bioavailability of R-(+)-6 (7.6 +/- 1.1%) appeared to be slightly lower than that of 2 (11.2 +/- 5.2%), although the in vitro metabolism of R-(+)-6 appeared to be slower than that of 2. Therefore first-pass metabolism was not thought to be the reason for the lower bioavailability of R-(+)-6, as compared to 2.

Animals↗
PubMed1995

History and future perspectives of the use of disinfectants in animal health.

Programmes for the prevention, control and eradication of animal diseases are closely interlinked in many ways. In the field of animal health over the last 100 years, surveillance, diagnostics, rapid response, regulatory and legal authorities, epidemiological investigations, together with guidelines for dealing with diseased animals and contaminated premises and materials, have proved to be the critical links in the chain of actions needed to prevent, control and eradicate diseases. Disinfection, as an integral part of the protection of animal health, has become more sophisticated and more effective over this period. The historical trends suggest that disinfection will be even more important in the future, and that disinfectants and procedures must be further developed to keep pace with new scientific findings, changing agricultural structures and contemporary social concerns.

Animal Diseases↗
PubMed1994

Effect of high fat diet on liver microsomal oxygenations in ferret.

1. Ferret on a high fat diet accumulated large amounts of fat in its liver and had blood acetoacetate and beta-hydroxybutyrate concentrations 250 and 375% of those in control animals. 2. The high fat diet alone increased ferret liver microsomal 7-ethoxyresorufin O-deethylase (EROD) activity by 90%, but had no effect on 7-methoxy-, 7-pentoxy-, or 7-benzyloxy-resorufin, O-dealkylase activities. Administration of 3-methylcholanthrene (MC) increased only liver EROD activity, by 5- to 6-fold, in ferret on both high fat and control diets. Induction of EROD, but not MROD activity, in ferret on the high fat diet indicates that P4501A1, but not P4501A2, is induced. 3. Activation of 3H-paracetamol, measured by covalent tissue binding to ferret liver microsomal fractions, was increased three-fold in ferret on the high fat diet, nine-fold by MC administered to ferret on a control diet, and 13-fold by MC given to ferret on the high fat diet. Similar results were obtained with activation of the cooked-food amine, Glu-P-1, by ferret liver microsomes. 4. Western blots with antibodies to rat liver P450s showed that ferret liver contains proteins orthologous with rat liver P4504A1 and bifunctional protein. However, whereas clofibrate, similar to high fat diets, induced these two proteins in rat liver, no increase of these proteins occurred in liver of ferret fed a high fat diet. Western blots also showed that ferret liver contains no P4501A1 or 1A2, and although these two proteins were induced by MC, no induction occurred when ferret was fed the high fat diet alone. Ferret liver microsomes also contain a protein recognized by rat anti-P4502E1 but of a lower molecular weight. 5. Immunosorbent (ELISA) analyses of ferret liver for P4501A1 and 4A1 showed that the high fat diet increased a protein orthologous to rat P4501A1 but did not increase any protein orthologous to rat P4504A1. 6. These findings indicate that the high fat diet does not induce ferret liver bifunctional protein or P4504A1 enzyme protein, but may enhance liver P4501A1 and 1A2 activities through the hyperketonaemia resulting from the high dietary fat. The conflicting P450 results, namely Glu-P-1 activation but no MROD activity for P4501A2, high EROD activity and ELISA quantification of P4501A1, but no positive Western blot, are probably due to differences in substrate specificity and immunological characteristics between rat and ferret enzymes.

Acetaminophen↗
PubMed1992

Hepatic mixed-function oxidases of ferret.

1. Ferret liver mixed-function oxidase enzymes have been quantified using a variety of substrates and the activities have been compared with those found in rat liver. 2. Ferret liver total cytochrome P-450 is only 30% of that of rat liver and exhibits higher 7-ethoxyresorufin O-deethylase (EROD) activity, and lower lauric acid hydroxylase activity than rat liver; other mixed-function oxidases are at similar levels of activity in both species. 3. Induction with 3-methylcholanthrene (MC), similar to MC-induction in rat, increases the total P-450 of ferret liver by 140%, but does not increase P-450 reductase or microsomal protein. EROD specific activity (pmol/min per mg protein) is increased 20-fold by MC treatment. 4. Turnover number of EROD for control liver microsomes of ferret, hamster, mouse, guinea pig and rat were 460, 69, 44, 36 and 35 pmol/min per nmol P-450, respectively, indicating the much higher value for ferret than for any of the rodent species studied. 5. Ferret liver EROD activity is inhibited by the P4501A1 inhibitor, alpha-naphthoflavone. Use of monospecific antibodies in ELISA, Western blot and enzyme-inhibition techniques has shown that EROD activity in ferret liver is attributable to two enzyme proteins orthologous with rat liver cytochromes P4501A1 and 1A2, with the former predominating. MC induces both P4501A enzyme proteins in ferret liver, as in rat liver, with P4501A1 activity predominating.

Animals↗
PubMed1990

Strain and sex differences in the response of mice to drugs that induce protoporphyria: role of porphyrin biosynthesis and removal.

A hepatic green pigment, inhibitory toward ferrochelatase, has been isolated from the liver of mice treated with griseofulvin, isogriseofulvin, or 3,5-diethoxycarbonyl-1,4-dihydrocollidine and has been shown to exhibit identical chromatographic characteristics to authentic N-methyl protoporphyrin. All four possible structural isomers have been demonstrated, and each drug produced primarily the same isomer. N-Methyl protoporphyrin has also been found in very small amounts in the liver of untreated mice, but the isomeric composition appeared to differ from that of the drug-induced N-methyl protoporphyrin. Intraperitoneal administration of 3,5-diethoxy-carbonyl-1,4-dihydrocollidine to female C3H/He/Ola and NIH/Ola inbred mice produced a marked dose-related loss of hepatic ferrochelatase activity, which was identical in magnitude in the two strains. Induction of hepatic 5-aminolevulinate synthase (ALA-S), and accumulation of liver protoporphyrin, however, were greater in C3H/He/Ola mice. The strain difference in ALA-S response was most marked when inhibition of ferrochelatase (the "specific" effect of the drug) was maximal, and this suggests that a genetic variation exists in the sensitivity of ALA-S to a second drug action, the so-called nonspecific action, which is shared by many lipid-soluble compounds. Male mice of three strains accumulated greater amounts of hepatic protoporphyrin than females after treatment with griseofulvin, yet no significant difference was found between the two sexes in the extent of ferrochelatase inhibition. Stimulation of ALA-S activity was slightly greater in males, but when porphyria was very marked, ALA-S activities were significantly lower in this sex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effects of glutathione depletion, chelation and diuresis on iron nitrilotriacetate-induced lipid peroxidation in rats and mice.

1. Rats and mice dosed with iron nitrilotriacetate (FeNTA) i.p. (2-12 mg Fe/kg) showed evidence of lipid peroxidation as indicated by increased exhalation of ethane and increased malondialdehyde formation in liver and kidney. 2. Buthionine sulphoximine (BSO) administered i.p. to rats and mice decreased the total glutathione (GSH) content of liver and kidney. When the rodents were pretreated i.p. with BSO prior to injection of FeNTA the increases in ethane exhalation, and in liver and kidney malondialdehyde production, were greater than with FeNTA alone, and the total GSH of liver and kidney were decreased. 3. Diuresis produced by i.p. administration of furosemide to mice substantially decreased the ethane exhalation resulting from FeNTA administration, had a lowering effect on kidney MDA, but had no significant effect on liver MDA production. 4. Similarly, desferrioxamine beta-mesylate administered i.p. to mice markedly decreased the ethane exhalation and kidney MDA production resulting from FeNTA administration.

Animals↗
PubMed1989

The effect of chronic parenteral administration of cadmium on isoenzyme levels of alkaline phosphate in intestinal mucosa.

Chronic administration of cadmium chloride to rats (13.3 mumol/kg body wt per dose subcutaneously) produced a decrease in the activity of alkaline phosphatase in the intestinal mucosa to less than half that in control rats by the time cumulative doses of between 30 and 48 mumol had been administered. The reduced level of activity remained approximately steady following further dosing. Three isoenzymes of intestinal alkaline phosphatase were separated electrophoretically. Chronic cadmium treatment markedly decreased the proportion of the 2 isoenzymes with lower electrophoretic mobility. Some analogies are drawn between the effect of cadmium administration, and magnesium deficiency on changes in intestinal alkaline phosphatase.

Alkaline Phosphatase↗
PubMed1989

Cysteine conjugate beta-lyase of rat kidney cytosol: characterization, immunocytochemical localization, and correlation with hexachlorobutadiene nephrotoxicity.

Cysteine conjugate beta-lyase (beta-lyase) was purified to electrophoretic homogeneity from the kidney cytosol of male Wistar rats. The highly purified enzyme exhibited a monomeric molecular weight of 50,000 Da and was active in the alpha-beta elimination of cysteine conjugates including S-(1,2-dichlorovinyl)-L-cysteine (DCVC), S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), and S-(2-benzothiazolyl)-L-cysteine, particularly toward DCVC and TFEC. The purified enzyme also exhibited glutamine transaminase K activity with phenylalanine and alpha-keto-gamma-methiolbutyrate as substrates. An antibody was raised to the purified rat protein in sheep and the crude immune serum affinity purified, yielding a specific antibody that recognized only the beta-lyase protein in whole kidney homogenates. Immunocytochemical studies on rat kidney sections stained with the purified antibody revealed that the cytosolic beta-lyase enzyme was mainly localized in the pars recta of the proximal tubule in untreated rats. This localization is coincident with the site-specific kidney necrosis produced by hexachloro-1,3-butadiene (HCBD). These results indicate that the tissue localization of beta-lyase in the proximal tubule plays an important role in determining the specific nephrotoxicity produced by halogenated alkenes such as HCBD.

Animals↗
PubMed1989

Effects of acute and sub-chronic administration of iron nitrilotriacetate in the rat.

Parenteral administration of iron nitrilotriacetate (FeNTA) to rats resulted in marked loss in body weight, and increases in liver/and kidney/body weight ratios. Fatalities, due to renal failure, depended on dosage and age of the animals, and were greater (70%) after a single large dose (12 mg iron) than after repeated smaller doses (30%). FeNTA administered subchronically gave rise to an increase in ethane exhalation, and to decreased liver glutathione peroxidase activity, and decreased cytochrome P-450 concentration and benzphetamine N-demethylase activity. It also resulted in severe renal tubular necrosis, with deposition of iron in the tubular cells and loss of brush border alkaline phosphatase activity, resulting in a dose-dependent diuresis, with increased urinary excretion of glucose, iron and lipid peroxidation products, and decreased urine creatinine concentration. NTA alone had none of these effects but slightly decreased the hepatic concentration of iron.

Acetates↗
PubMed1989

The measurement of d-fenfluramine and its metabolite, d-norfenfluramine in plasma and urine with an application of the method to pharmacokinetic studies.

1. A specific and sensitive gas chromatographic assay is described for the measurement of d-fenfluramine and its de-ethylated metabolite, d-norfenfluramine, in biological fluids, together with some data on its application to the oral pharmacokinetics of the drug. 2. The analytical method developed has advantages over the previously described methods since it uses nitrogen specific detection and, when applied routinely, enables smaller sample volumes to be used (typically 1 ml of plasma) with a shorter chromatography time and an improved sensitivity (minimum quantifiable level of 2.5 ng ml-1). 3. Peak plasma concentrations of 22 and 24 ng ml-1 of intact drug were reached at 4 h after an oral dose of 14C-d-fenfluramine hydrochloride (30 mg) given to two volunteers as part of a metabolism and disposition study. Subsequently, concentrations of intact drug declined monoexponentially with a half-life of approximately 13 h. Peak concentrations of 10 and 8 ng ml-1 of the metabolite, d-norfenfluramine, were reached after 4 and 6 h and were maintained as a plateau for a further 4-6 h. Assessment of the half-life of the metabolite could not be made because of lack of data on the terminal portion of the curves. 4. The urinary excretion of d-fenfluramine (6.0 and 10.6% of the dose) and d-norfenfluramine (5.8 and 8.8% of the dose) was low, indicating extensive metabolism of the parent drug.

Administration, Oral↗
PubMed1989

The degradation of haem by carbon tetrachloride: metabolic activation requires a free axial coordination site on the haem iron and electron donation.

1. The ability of haem to catalyse the reductive activation of carbon tetrachloride (CCl4) in vitro has been investigated under anaerobic conditions, using methaemalbumin (MHA) and either sodium dithionite or NADPH together with NADPH-cytochrome P-450 reductase (EC 1.6.2.4) as the reducing agents. 2. In the non-enzymic system protohaem and other non-physiological haem analogues underwent rapid and extensive CCl4-dependent degradation, due to irreversible modification of their porphyrin tetrapyrrolic structure. 3. This mechanism of non-enzymic activation of CCl4 by protohaem mimics that catalyzed by cytochrome P-450 in that it requires a free, reduced haem iron and electron donation and it is largely prevented by carbon monoxide. 4. H.p.l.c. analysis of 14C-haem after anaerobic incubation with CCl4 and sodium dithionite gave radioactive products which eluted before and after haem, and exhibited significantly lower absorbance at 400 nm compared with authentic haem. When the products of CCl4-dependent haem degradation were methylated and applied to silica for t.l.c., two non-fluorescent pigments were isolated, purified and partially characterized. 5. On incubation of haem with 14CCl4 and sodium dithionite a 1:1 stoichiometry could be calculated for haem loss and 14CCl4-derived adduct formation, indicating that, as with microsomes, the loss of haem may be the result of a typical 'suicidal' inactivation reaction where the same haem moiety is both the site of CCl4 activation and the target of CCl4 reactive metabolites.

Animals↗
PubMed1988

The mechanism of the suicidal, reductive inactivation of microsomal cytochrome P-450 by carbon tetrachloride.

1. Stoichiometric losses of microsomal haem and cytochrome P-450 were observed when carbon tetrachloride (CCl4) was incubated anaerobically with rat liver microsomes using NADPH or sodium dithionite as a reducing agent. A rapid destruction of haem was also observed during the non-enzymatic reductive incubation of CCl4 with soluble haem preparations (methaemalbumin) in presence of sodium dithionite. The results indicate that haem is both the site and the target of the suicidal activation of CCl4 by cytochrome P-450. 2. When an additional, fluorimetric assay for haem determination was used, an equimolar loss of protoporphyrin IX fluorescence was also observed in both the enzymatic and non-enzymatic system, indicating that the haem moiety of cytochrome P-450 has undergone a structural change, involving either loss or labilization of the porphyrin tetrapyrrolic structure. In both systems the loss of porphyrin was prevented by carbon monoxide (CO). 3. A dichlorocarbene-cytochrome P-450 ligand complex is partially responsible for the difference spectrum obtained on addition of CCl4 to anaerobically reduced rat liver microsomes. A molar extinction coefficient for this complex has been calculated. The carbene trapping agent 2,3-dimethyl-2-butene (DMB) strongly inhibited (greater than 95%) the formation of this spectrum but did not modify the loss of haem in reduced CCl4-supplemented microsomal incubations. The results suggest that dichlorocarbene (:CCl2) is not significantly involved in CCl4-dependent haem destruction. 4. Pretreatment of rats with different microsomal enzyme inducers was responsible for similar but not identical patterns of :CCl2 and CO formation and haem loss during incubation of CCl4 with reduced microsomes. This indicates a critical role of CCl4 metabolism in the suicidal destruction of cytochrome P-450 haem and suggests that the apoprotein of cytochrome P-450 is capable of modulating not only the metabolism of CCl4 to :CCl2 but also the hydrolysis of :CCl2 to CO. 5. Inactivation of cytochrome P-450 by CCl4 with reduced microsomes from Aroclor-pretreated rats was saturable and followed pseudo first-order kinetics. This provides further evidence to conclude that CCl4 activation is a suicidal process where the reactive metabolite(s) formed bind to haem, we predict, in a one to one stoichiometry. 6. The partition ratio between loss of cytochrome P-450 haem and CCl4 metabolism by liver microsomes from Aroclor pretreated rats has been investigated using limiting concentrations of CCl4. It was calculated that approximately 26 molecules of CCl4 had to be metabolised to achieve the loss of one molecule of haem.

Animals↗
PubMed1988

The induction of autoxidative tissue damage by iron nitrilotriacetate in rats and mice.

Iron nitrilotriacetate (FeNTA) is a potent initiator of lipid peroxidation, and, when injected intraperitoneally into mice, it greatly increased ethane and pentane exhalation within 30 min. The time course and dose-response of the exhalation of ethane were studied and compared with the increase in tissue malondialdehyde (MDA) production. Production of MDA was greater in mouse kidney than liver and correlated better with the exhalation of ethane. In rats FeNTA also increased ethane exhalation and MDA, but the rat was less susceptible than the mouse to FeNTA toxicity. MDA production was greater in rat liver than kidney and both correlated well with ethane exhalation (r = 0.97 and 0.98, respectively). Renal proximal tubular damage was observed histologically 35 min after mice were given FeNTA, but in rats the lesion appeared 24 hr after dosage. Histopathological assessment of kidney damage at these times showed fair correlation with ethane exhalation in mice (r = 0.73) and rats (r = 0.62), respectively. Activities of kidney brush-border marker enzymes were decreased in mice, 35 min after FeNTA administration, and showed a similar trend in rats. Some rats also showed periportal necrosis of the liver, 24 hr after FeNTA administration. The very rapid onset of autoxidative damage suggests that FeNTA itself is the causative agent rather than subsequently formed, less reactive complexes, such as transferrin. The site of damage in the kidney tubule is consistent with the region of concentration of filtered FeNTA. It is suggested that FeNTA supports the formation of superoxide ion from dissolved oxygen and may be responsible for the subsequent formation of hydroxyl radical which initiates lipid peroxidation. The species difference between rat and mouse may be due to the greater resistance of the rat kidney to FeNTA-induced autoxidative damage.

Alkanes↗
PubMed1988

Possible role of intracellular Ca2+ in the toxicity of phenformin.

Selective use of various mitochondrial Ca2+ transport inhibitors indicated that significant Ca2+ redistribution may occur during the isolation of mitochondria. Exposure of guinea-pig liver mitochondria to phenformin (beta-phenethylbiguanide) during the isolation procedure resulted in decreased mitochondrial Ca2+. Novel isolation conditions were developed to determine liver mitochondrial calcium content considered to reflect that in vivo. Administration of phenformin to rats and guinea-pigs resulted in decreased mitochondrial Ca2+. Decreased liver mitochondrial Ca2+ correlated inversely with raised blood lactate concentrations in the guinea-pig; 2-oxoglutarate, but not succinate oxidation, was inhibited in these mitochondrial preparations. A mechanism of action for phenformin-associated lactic-acidosis, attributable to impaired mitochondrial function arising from inactivation of Ca2+-sensitive, NAD+-dependent mitochondrial dehydrogenases (e.g. 2-oxoglutarate dehydrogenase) due to alteration in mitochondrial calcium content, is proposed.

Animals↗
PubMed1987

The effect of sodium aurothiomalate (myochrysin) on the distribution of calcium, magnesium, copper, zinc and iron in the rat.

Sodium aurothiomalate was given to male Wistar rats (initial body weights: 150 g) by subcutaneous (s.c.) injection at doses of up to 7.5 mg/kg (corresponding to 4.27 mg gold/kg), twice a week, for 4-5 weeks. The concentrations of Ca, Mg, Fe, Cu and Zn were measured in serum, urine, faeces and in the liver, kidney, spleen, heart, lung, testis, bone and muscle. Kidney cytosol was separated by gel chromatography and the fractions analysed for protein, copper, zinc, iron and gold concentrations. The concentration of copper was increased 5-fold in kidney while smaller increases of zinc in kidney, copper in muscle, iron in muscle and testis and calcium in spleen were found. There was a significant reduction in the concentration of copper in serum. Kidney cytosol from gold-treated but not from control animals contained a low molecular weight protein which was associated with copper, zinc and gold. The rats developed proteinuria and microscopic changes to renal tubular cell structure were also observed. It is suggested that the gold-induced accumulation of copper may follow from an increased rate of synthesis of metallothionein and could be responsible for the renal dysfunction which develops in a proportion of rheumatoid arthritis patients who are treated with gold.

Animals↗
PubMed1987

The metabolism of 14C-DDT, 14C-DDD, 14C-DDE and 14C-DDMU in rats and Japanese quail.

The metabolism and excretion of 14C-DDT, 14C-DDD, 14C-DDE and 14C-DDMU were compared in male rats and male Japanese quail after i.p. injection. The rate of excretion of radioactivity was greater in the rat than in the quail for all compounds except DDMU. Skin and fat were major sites of residual radioactivity in both species, the compound administered and DDE accounting for most of the radioactivity except in the case of DDMU. The four radiolabelled compounds were all present in significant quantities in excreta of both species in unchanged forms. The metabolic patterns for DDT and DDD were similar in rat and quail, except that the rat formed 2,2-di(4-chlorophenyl)ethanol (DDOH) from DDT while the quail did not. Rat and quail metabolized DDE and DDMU differently. Ring-hydroxylated derivatives of DDE were formed only in the rat and analogous metabolites of DDMU were produced only by quail. Both species produced di(4-chlorophenyl)acetic acid as a metabolite of all four compounds administered, although the formation was generally less and slower in quail than rat. Comparative metabolism of DDMU with the other compounds indicated that this compound is not a metabolic intermediate in the metabolism of DDT in either rat or quail.

Animals↗