Biomedical subjects

J C Phillips

Publications and source records attributed to J C Phillips.

At least 55 records · Page 3Linked to original sources

PubMed1986

A single-dose pharmacokinetic study of the antisickling agent cetiedil.

Cetiedil citrate is an antisickling agent shown to be effective in reducing the severity and duration of acute sickle cell crisis. With the use of a sensitive GC/MS assay, the pharmacokinetic profile of cetiedil was studied in normal men and in men with sickle cell anemia who were not in crisis at the time of study. A peak cetiedil concentration of 70 to 200 ng/ml was found immediately after a 30-minute drug infusion. The plasma level then gradually declined to approximately 10 ng/ml during a 3-hour distributive phase. Computer analysis of the data was most consistent with a three-compartment model. No pharmacokinetic differences were found between the normal men and the subjects with sickle cell. Because the cetiedil plasma levels achieved during this in vivo study are well below concentrations that exhibit antisickling activity in vitro, additional clinical studies will be necessary before an optimal dosing regimen can be established.

Adult↗

PubMed1984

A proposal for the metal geometry in yeast superoxide dismutase based on results from EXAFS spectroscopy.

Extended x-ray absorption fine structure (EXAFS) spectra have been recorded at the Cu edge and Zn edge in native yeast superoxide dismutase and at the Cu edge and Cd edge in the yeast superoxide dismutase derivative, where Zn has been substituted with Cd. Two different metal ligand distances in the range 1.9-2.0 A and 2.3-2.4 are determined for the Cu and Zn metals. For Cd in the Zn site two different metal ligand distances about 2.2 A and 2.6 A, respectively, were found. The striking feature is the similarity between the amplitude and radii determined for both the Cu and Zn sites. The increased distances for Cd can be explained by the increased ionic radius of Cd relative to Cu and Zn. Based on these EXAFS results and other relevant knowledge about the metal geometries, we propose that histidine 61 (63) positioned between the Cu and Zn metals are in one subunit bound to Zn and in the other to Cu. This model explains the recently observed difference between the two metal sites in each subunit.

Copper↗

PubMed1983

Oxygen binding by Helix pomatia alpha-haemocyanin studied by X-ray-absorption spectroscopy.

The X-ray absorption spectra of haemocyanin from Helix pomatia were obtained by using X-rays from synchrotron radiation. Cu K-edges were recorded at four conditions, namely fully oxygenated, 85% oxygenated, 12% oxygenated and fully deoxygenated. The percentage oxygenation calculated from the edge-shift of the partially oxygenated samples did not agree with the percentage oxygenation as determined by u.v. measurements. Two intermediates in the oxygenation process are presented to explain the observed dissimilarities.

Animals↗

PubMed1983

Studies of the metabolic bioactivation of n-nitrosopyrrolidine in the rat.

The metabolism of N-nitrosopyrrolidine (NPYR) to 4-hydroxybutanal (4-HB) (the first stable product of the putative alpha-hydroxylation pathway) and its bioactivation in the Ames bacterial mutagenicity test system were examined in the presence of a number of inhibitors. Both SKF 525A and piperonyl butoxide were found to be potent inhibitors of the production of 4-HB by rat liver microsomal preparations but were ineffective in the mutagenicity model with liver S-9 from either untreated or Aroclor 1254 pretreated rats. In addition two inhibitors of the mutagenic activity of N-nitrosodimethylamine (NDMA) in this system, 2-phenylethylamine and benzimidazole failed to reduce the activity of NPYR. These results suggest that the bioactivation of NPYR may proceed by processes other than the cytochrome P-450 dependent route generating 4-HB and the amine oxidase catalysed route implicated in NDMA activation. Evidence was also obtained of a second cytosol dependent bioactivation step involving a microsome generated pre-mutagen. This activity may be responsible, at least in part, for the enhancement by cytosol of the mutagen producing activity of liver microsomes from Aroclor 1254 pretreated (but not control) rats.

Animals↗

PubMed1983

Rat endometrial bioelectric activity in vivo and in vitro: effects of adrenaline.

The transuterine potential difference (p.d.) generated by the endometrium was measured in vivo in anaesthetized, ovariectomized rats treated with 10 micrograms oestradiol-17 beta each day for 3 days. Intravenous injection of adrenaline induced transient hyperpolarization of the p.d.; sigmoid dose-dependency was observed over the range 2-40 micrograms/kg. Pre-treatment of the rats with syrosingopine shifted the dose-response curve to the left (enhancement) while combined propranolol (800 micrograms/kg) and phentolamine (800 micrograms/kg) shifted the dose-response curve to the right (depression). Isoprenaline gave similar quantitative changes in the p.d. in vivo which displayed a similar time course and sigmoid dose-dependency. Propranolol alone (800 micrograms/kg) shifted this dose-response curve significantly to the right. Addition of adrenaline or isoprenaline to the serosal solution bathing uteri incubated in vitro after removal from oestradiol-treated rats induced changes in endometrial bioelectric activity that exhibited sigmoid dose-response curves for the transuterine p.d. and short-circuit current (Isc). Propranolol significantly shifted the dose-response curves for adrenaline to the right. Only adrenaline caused small but significant decreases in the uterine resistance but these were not dose-dependent. Acetylcholine, 5-hydroxytryptamine, noradrenaline and phenylephrine had no effect on the transuterine p.d. in vivo or in vitro or on the Isc in vitro. No significant electrical changes could be induced by adrenaline or any of the other drugs across the uteri from untreated ovariectomized rats either in vivo or in vitro. The transluminal membrane p.d. of surface endometrial cells measured with micro-electrodes was depolarized by an addition of serosal adrenaline but only 41% of the cells successfully impaled responded in this way. The results indicate that endometrial cells under oestrogen stimulation possess electrogenic processes that can be modulated specifically by adrenaline through the mediation of a serosally sited beta-adrenoceptor. The physiological role of the mechanism has yet to be established.

Animals↗

PubMed1983

Acute calculous cholecystitis with patent cystic duct.

In the diagnosis of acute cholecystitis, the interpretation of cholescintigraphy is usually not difficult. It is conceivable, however, that with unusual location of obstructing calculi atypical images could result. Three cases were studied with cholescintigraphy and one with cholecystography in which more distal locations of obstructing calculi resulted in partial visualization of the gallbladder and erroneous interpretations were possible. Nuclear medicine radiologists should, therefore, be aware that atypical gallbladder images may be the result of unexpected location of obstructing calculi. Clues for assisting in interpretation are offered.

Acute Disease↗

PubMed1982

Zinc-sulfur bonds of aspartate transcarbamylase studied by x-ray absorption spectroscopy.

X-ray absorption spectra have been recorded for aspartate transcarbamylase [unligated and ligated with the transition-state analogue N-(phosphonoacetyl)-L-aspartate] and for the model compound zinc dimethyldithiocarbamate. The spectra confirm that, in the enzyme, the zinc atom is ligated to four sulfur atoms, with a mean distance of 2.34 +/- 0.03 A. A spread in bond lengths of 0.1 +/- 0.03 A is possible, due to thermal and/or static disorder. No significant difference was found between the spectra of the ligated and unligated enzymes.

Aspartate Carbamoyltransferase↗

PubMed1982

The metabolic disposition of 14C-labelled Ponceau 4R in the rat, mouse and guinea-pig.

The absorption, metabolism and excretion of 14C-labelled Ponceau 4R has been studied in the rat, mouse and guinea-pig. Following administration of a single oral dose of 0.5 or 50 mg/kg body weight substantially all of the dose was excreted in the urine and faeces within 72 hr, with the majority being accounted for in the faeces. In all three species, naphthionic acid was the major urinary metabolite, whereas in the faeces naphthionic acid, 7-hydroxy-8-aminonaphthalene-1,3-disulphonic acid and unchanged dye were found. Pretreating male rats with unlabelled Ponceau 4R in the diet (50 mg/kg/day) for 28 days prior to dosing with the 14C-labelled colouring had no effect on the route of excretion or the time taken to eliminate the majority of the label. Following a single dose of 14C-labelled colouring to previously untreated rats, mice and guinea-pigs or to rats pretreated as above, no marked accumulation of radioactivity in any tissue was found, although tissue levels of radioactivity at 72 hr after dosing were higher in the pretreated rats than in those that were not pretreated. Pregnant rats eliminated a single oral dose of 14C-labelled colouring at a similar rate to non-pregnant females; however, some retention of radioactivity in the foetuses was found. In studies of absorption from isolated loops of small intestine containing 50, 500 or 5000 ppm Ponceau 4R, no significant absorption was detected in rats, but some absorption was seen in mice at the lowest concentration, and in the guinea-pig at the two higher concentrations.

Animals↗

PubMed1982

Studies on the metabolism of dimethylnitrosamine in vitro by rat-liver preparations. II. Inhibition by substrates and inhibitors of monoamine oxidase.

1. The metabolism of dimethylnitrosamine (DMN) to formaldehyde by rat-hepatic postmitochondrial supernatant fractions has been compared with the activities of several cytochrome P-450-dependent mixed-function oxidase enzymes and the Ziegler mixed-function amine oxidase enzyme (EC 1.14.13.8). 2. A variety of monoamine oxidase (MAO, EC 1.4.3.4) inhibitors of diverse chemical structure inhibited the metabolism of DMN. In parallel studies a number of MAO substrates, but not their deaminated products, also inhibited DMN metabolism, whereas substrates of diamine oxidase were ineffective. 3. At concentrations which inhibited DMN metabolism several MAO substrates and inhibitors did not inhibit the N-oxidation of N, N-dimethylaniline and an inhibitor and an activator of the Ziegler enzyme had no corresponding effect on DMN metabolism. 4. The metabolism of DMN and a number of MAO enzyme activities were stable to storage under conditions where mixed-function oxidase enzymes were not. 5. These results are consistent with the suggestion that DMN may, at least in part, be metabolized by hepatic enzyme(s) not dependent on cytochrome P-450 and that a microsomal amine oxidase enzyme, unrelated to the Ziegler enzyme, may be involved in the hepatic degradation of this nitrosamine. The present data does, however, suggest a role for microsomal NADPH-cytochrome c reductase in hepatic DMN metabolism.

Amine Oxidase (Copper-Containing)↗

PubMed1982

Studies on the metabolism of dimethylnitrosamine in vitro by rat-liver preparations. III. Effect of cobaltous chloride treatment.

1. The effects of CoCl2 administration to rats on xenobiotic metabolism, dimethylnitrosamine (DMN) metabolism to formaldehyde and methanol, and monoamine oxidase (MAO) enzyme activities in hepatic subcellular fractions have been studied. 2. CoCl2 treatment markedly decreased hepatic mixed-function oxidase enzyme activities and microsomal cytochrome P-450 content. In contrast, the N-oxidation of N, N-dimethylaniline and the activity of microsomal NADPH-cytochrome c reductase was unaffected. 3. The metabolism of DMN to formaldehyde by postmitochondrial supernatant fractions was decreased at substrate concn. of 0 . 5, 5 and 50 mM by CoCl2 treatment but the metabolism of 5 and 50 mM DMN to methanol was affected less. 4. CoCl2 had little effect on MAO activities in whole homogenates, but microsomal MAO activities were markedly inhibited. 5. The inhibition of microsomal MAO indicates that CoCl2 is not a specific inhibitor of cytochrome P-450-dependent biotransformations and consequently the inhibition of DMN metabolism is not evidence of a wholly cytochrome P-450-dependent process.

Animals↗

PubMed1982

Studies on the metabolism of dimethylnitrosamine in vitro by rat-liver preparations. I. Comparison with mixed-function oxidase enzymes.

1. The metabolism of dimethylnitrosamine (DMN) to formaldehyde by rat-liver preparations has been studied at substrate concn. of 0.5, 5 and 50 mM and compared with mixed-function oxidase enzyme activities. 2. The microsomal metabolism of low (0.5 and 5 mM) and high (50 mM) substrate concn. of DMN was differentially affected by acetone addition or KI treatment. 3. A series of heterocyclic compounds related to pyrazole were potent inhibitors of metabolism of 0.5 and 5 mM DMN at concn. which had little effect on mixed-function oxidase activities. In contrast, purine addition slightly stimulated the metabolism of low but not high concn. of DMN. 4. The results are consistent with the suggestion that multiple enzymic pathway(s) are involved in hepatic DMN metabolism and that some of these pathway(s) may be independent of cytochrome P-450.

Acetone↗

PubMed1982

Inhibition of dimethylnitrosamine metabolism by some heterocyclic compounds and by substrates and inhibitors of monoamine oxidase in the rat.

Pretreatment of rats with a number of nitrogen-containing heterocyclic compounds was found to inhibit markedly the metabolism of dimethylnitrosamine (DMN) in terms of both CO2 excretion and decline in blood DMN concentration. However, many of these compounds had either much less or no inhibitory effect on the in vivo metabolism to CO2 of a typical mixed-function oxidase substrate, aminopyrine. In addition, a number of model inhibitors of monoamine oxidase (MAO) activity also inhibited DMN metabolism in the intact animal, and a number of primary amines, known substrates of hepatic MAO, inhibited DMN metabolism but not that of aminopyrine in the isolated perfused liver system. These results, together with in vitro data and previously reported studies on the effect of MAO inhibitors and substrates on the mutagenicity of DMN, suggest that the metabolism and bioactivation of DMN may be in part mediated by a MAO type of enzyme activity.

Aminopyrine↗

PubMed1981