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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
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

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 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

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↗
PubMed1979

Combined high-performance liquid chromatography and radioimmunoassay method for the analysis of delta 9-tetrahydrocannabinol metabolites in human urine.

A high-performance liquid chromatography-radioimmunoassay method for the measurement of cannabinoids in urine is described. The method involves chromatographing a hydrolysed urine sample with high-performance liquid chromatography and quantifying the eluting cross-reacting cannabinoids with radioimmunoassay. It has been applied to the analysis of cannabinoids in human urine obtained from subjects who had smoked delta 9-tetrahydrocannabinol and the identities of some of the cross-reacting cannabinoids have been established by gas chromatography-mass spectrometry. The method is suitable for use as a routine procedure for cannabinoid analysis in urine.

Chromatography, High Pressure Liquid↗
PubMed1979

The early effects of chemical carcinogens on adult rat hepatocytes in primary culture: I. Quantitative changes in intracellular enzyme activities following a single dose of carcinogen.

The effects of exposure of adult rat hepatocytes to chemical carcinogens have been studied using a short-term maintenance culture system. Scanning microdensitometry was used to quantitate the observed changes in enzyme activity. The dose-response curves showed a biphasic response for all 4 enzymes studied (glucose-6-phosphate dehydrogenase, succinate dehydrogenase, NADPH oxidase and gamma-glutamyl transpeptidase) there being decreased enzyme activities at the higher dose levels used, possibly indicating cytotoxicity. The enhancement of enzyme activity at low dose levels was due to generalised increases occurring in every cell, rather than to selection of a cell species particularly high in enzyme activity. A culture period of 24 h was necessary for the complete adaptation of the cells to the culture environment as evidenced by the response of intracellular glucose-6-phosphate dehydrogenase activity to carcinogen treatment. These findings are discussed in relation to previously reported in vivo studies.

Animals↗
PubMed1979

The early effects of chemical carcinogens on adult rat hepatocytes in primary culture. II. Effects on unscheduled DNA synthesis, cell division and alpha-fetoprotein production.

The effects of exposure of rat hepatocytes in primary maintenance culture to chemical carcinogens has been studied with respect cytotoxicity and alterations in mitotic index, unscheduled DNA synthesis and alpha-fetoprotein (AFP) production. All compounds tested produced cytotoxicity. Increases in mitotic index and unscheduled DNA synthesis and the production of AFP were observed after treatment of the cells with the carcinogens but not after treatment with the non-carcinogenic isomers. These increases were dose-dependent and depended on the time of exposure and the time incubated postexposure. The patterns of the increase in mitotic index and AFP production after cessation of carcinogen exposure were very similar, with the increase in mitotic index occurring slightly before that for the AFP production and it is suggested from this and other data that the production of AFP is dependent on the generation of a cell species functionally distinct from the non-dividing hepatocytes. It is also suggested that measurement of unscheduled DNA synthesis in conjunction with that of AFP production in cultured hepatocytes may be useful as part of a screening programme for chemical carcinogens.

Animals↗
PubMed1979

The tissue disposition and urinary excretion of cadmium, zinc, copper and iron, following repeated parenteral administration of cadmium to rats.

The effect of repeated parenteral administration of cadmium (0.75, 1.5 and 3.0 mg/kg) on tissue disposition and urinary excretion of cadmium, zinc, copper and iron has been studied in the male rat. Cadmium, zinc and copper accumulated in liver and kidney, but the concentration of iron did not alter significantly. The kidney weight relative to body weight showed a dose-related increase in weight of 25--65%. Excretion of cadmium in the urine increased directly with dosage and the increase was most significant when kidney damage had probably occurred. Administration of cadmium also resulted in dose-related increases in the urinary excretion of zinc, copper and iron. The cadmium concentration of blood increased with dosage of cadmium, and the plasma concentrations of zinc and copper were also raised but plasma iron concentration was diminished.

Animals↗
PubMed1979

Appropriateness of drugs prescribed by primary care physicians for depressed outpatients.

In a sample of middle class individuals seeking martial and sexual counseling, 30% had diagnosable psychiatric illness, including 14% who had depressions at the time of interview. Those with psychiatric syndromes were significantly more likely to have prescribed psychoactive than those without these syndromes. Those with depression were more likely to have received diazepam and similar drugs than antidepressants. The same was true for those with other syndromes but in many of these cases, diazepam or other antianxiety agents seemed more appropriate. Thus, affective disorder might well be the psychiatric syndrome for which these drugs are most often inappropriately prescribed. Inappropriate treatment is a matter of concern in an illness which is potentially fatal.

Adult↗
PubMed1979

Metabolism of phenformin in the rat and guinea-pig.

1. Following administration of [2'-14C]phenformin to rat and guinea pig, the guinea-pig showed a slower rate of excretion of radioactivity than the rat, together with a slower rate of metabolism, which may partly explain the increased pharmacological response of the guinea-pig to the drug. 2. The rat eliminated 26% of an intraduodenal dose of [2'-14C]phenformin (20 mg/kg) in the bile in 6 h compared to 6% in the guinea-pig. 3. The rat excreted large amounts of 4-hydroxyphenformin (free and conjugated with glucuronic acid) and also some unchanged phenformin, but the extent of metabolism varied with dose and route of administration. 4. The guinea-pig excreted no 4-hydroxyphenformin after an oral dose (25 mg/kg) and only a small amount after i.p. administration (12.5 mg/kg). After oral administration, guinea-pig urine contained an unidentified metabolite, and its glucuronide, which may be a product of aliphatic C- or N-hydroxylation and which accounted for 47% of the 24 h urinary radioactivity (17% of the dose). Guinea-pig faeces contained an unidentified metabolite which had similar chromatographic properties to the novel urinary metabolite.

Administration, Oral↗
PubMed1978

Combined high-pressure liquid chromatography and radioimmunoassay method for the quantitation of delta 9-tetrahydrocannabinol and some of its metabolites in human plasma.

A high-pressure liquid chromatography-radioimmunoassay (HPLC-RIA) method for the measurement of cannabinoid levels in plasma is described. The method is capable of quantifying 0.1 ng of a cannabinoid in 1 ml of plasma. The experimental procedure consists of an initial separation of cannabinoids in a plasma extract by HPLC followed by collection of the HPLC eluate and RIA. A chromatogram consisting of the cross-reacting cannabinoids in plasma may then be constructed. The plasma concentrations of cannabinoids with retention volumes equivalent to those of delta 9-tetrahydrocannabinol, cannabinol and mono-hydroxylated metabolites have been measured by this technique.

Chromatography, Gas↗
PubMed1978

The anaerobic dechlorination of trichlorofluoromethane by rat liver preparations in vitro.

Incubation of trichlorofluoromethane with a liver microsomal fraction and an NADPH generating system under anaerobic conditions produced a metabolite dichlorofluoromethane, characterised by gas chromatography and mass spectrometry. The metabolic reaction was carried out by liver microsomes from the mouse, rabbit, hamster and rat and was increased by phenobarbitone pre-treatment. The formation of dichlorofluoromethane in vitro was enhanced by the addition of FMN, but partially inhibited by the presence of air, oxygen, SK&F 525-A, metyrapone and carbon tetrachloride and totally inhibited by carbon monoxide. The consumption of NADPH in the reaction was greater than could be accounted for by the production of dichlorofluoromethane indicating the possible formation of other metabolic products. It is suggested that trichlorofluoromethane interacts with the reduced form of cytochrome P-450 at the oxygen binding site and a possible mechanism for its subsequent reductive dechlorination is proposed.

Aerosol Propellants↗