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Biomedical subjects

F M Williams

Publications and source records attributed to F M Williams.

At least 73 records · Page 4Linked to original sources
PubMed1993

Fate of fluazifop butyl in rat and human skin in vitro.

Enzyme mediated hydrolysis of fluazifop butyl has been measured with rat and human skin post-mitochondrial fractions. Rat skin had a ten times greater capacity to metabolise fluazifop butyl than human skin, but the enzyme affinities were similar. The post-mitochondrial fraction metabolism was compared to that seen during absorption in a flow through diffusion cell with viable skin. Limited hydrolysis of absorbed fluazifop butyl was seen in rat skin, but increased two fold if the stratum corneum was removed. The stratum corneum was found to retain fluazifop butyl. When the skin was pre-incubated with the esterase inhibitor bis (p-nitrophenol) phosphate (BNPP), reduced metabolism was seen. No metabolism of fluazifop butyl was seen in human skin during absorption. Retention of the compound by the stratum corneum is postulated to restrict the accessibility of the compound to the enzyme site, thus influencing the observed metabolism during the absorption process.

Animals↗
PubMed1993

Paraoxonase distribution in Caucasian males.

Mean plasma paraoxonase activity was lower in a population of all males than in a mixed sex population with no evidence of the higher activity group. It is suggested that sex differences in plasma lipid may contribute to the observed differences, and that factors other than genetics may influence observed plasma paraoxonase levels.

Adolescent↗
PubMed1993

Peripheral esterases in the rat: effects of classical inducers.

Liver microsomal paraoxonase, aryl esterase and fluazifop butyl esterase (carboxylesterase) were induced by pretreatment of rat with phenobarbitone but not by beta-naphthoflavone or clofibric acid. In the extrahepatic tissues lung cytosolicfluazifop butyl and phenylacetate esterase were induced.

Animals↗
PubMed1993

The effects of cadmium and zinc interactions on the accumulation and tissue distribution of zinc and cadmium in lettuce and spinach.

The interactions between Zn and Cd on the concentration and tissue distribution of these metals in lettuce and spinach were studied at levels corresponding to background and Zn-Cd contaminated sites. Plants were grown in nutrient solutions containing 0.398-8.91 microM Zn and 0.010-0.316 microM Cd. Cadmium accumulated more in old than in young leaves of both crops at any solution Cd level, whereas Zn followed that pattern only at Zn levels > or = 3.16 microM. Increasing solution Cd increased Zn concentrations in young leaves of lettuce but not of spinach, regardless of Zn levels. Cadmium concentrations in young leaves of both crops decreased exponentially with increasing solution Zn at low (0.0316 microM) but not at high (0.316 microM) solution Cd. The Zn: Cd concentration ratios in young leaves of lettuce and spinach grown at 0.316 microM Cd became greater as the solution Zn increased. Cadmium and Zn concentrations in young leaves were related more closely to the relative concentrations of Zn and Cd in solution than were the concentrations in old leaves, especially in lettuce. Studies of Zn-Cd interactions and Cd bioavailability should differentiate between basal and upper leaves of lettuce and spinach. Compared to Cd-only pollution, Zn-Cd combined pollution may not decrease Cd concentrations in lettuce and spinach edible tissues, but because it increases their Zn concentrations it lowers plant Cd bioavailability.

Journal Article↗
PubMed1993

Trimetazidine inhibits neutrophil accumulation after myocardial ischaemia and reperfusion in rabbits.

Interventions that inhibit neutrophil infiltration into myocardial tissue after ischaemia and reperfusion are reported to reduce the size of the infarct. We examined whether administration of trimetazidine, which is reported to reduce myocardial infarct size, affects this process. [111In]Neutrophils and [125I]albumin were administered intravenously (i.v.) to anaesthetized rabbits to allow measurement of cell accumulation and changes in microvascular plasma protein leakage. A 30-min period of coronary artery occlusion followed by 3-h reperfusion was used, and the area at risk (AR) myocardium was defined by dye exclusion. Twelve rabbits received 2.5 mg/kg trimetazidine i.v., 10 min before coronary artery occlusion; the 13 controls received saline. In the control group, the number of [111In]neutrophils/g tissue in the AR (30,591 +/- 6,725) was significantly greater than in the normal zone (NZ, 11,519 +/- 1,605, p < 0.01). In the trimetazidine-treated group, the number of [111In]neutrophils in the AR was significantly lower than in the control group (12,717 +/- 1,958 [111In]neutrophils/g, p < 0.01). There was no significant difference in neutrophil content of the NZ (7,832 +/- 1,117 [111In]neutrophils/g) in treated animals as compared with that in control. Accumulation of [111In]neutrophils in response to intradermal administration of leukotriene B4, interleukin-8 (IL-8), or zymosan-activated plasma was not affected by the drug. The effect of trimetazidine on neutrophil accumulation into post-ischaemic reperfused myocardium therefore does not appear to result from a direct action on the neutrophil.

Animals↗
PubMed1993

The effect of age and frailty upon blood esterase activities and their response to dietary supplementation.

1. The aims of this study were two-fold. First, to define ranges of blood esterase activities in three groups, namely young subjects, fit community dwelling elderly and frail, chronically hospitalised elderly subjects, and second, to determine whether low blood esterase activities in the frail patients could be altered by increasing their nutritional intake. 2. Plasma cholinesterase, aspirin esterase, paraoxonase and phenylacetate esterase activities were all significantly lower in the frail elderly compared with the young and fit elderly volunteers. The activity of red blood cell esterase was not different in the frail elderly. 3. Fourteen frail elderly patients were randomly assigned to receive either hospital meal provision plus supplemental feeding with Build-up (Nestle) and Maxijul (SHS Ltd) or hospital provision alone for 8 weeks. Dietary intake was measured for all patients at the start of the study and at week 8. Measurements of blood esterase (cholinesterase, phenylacetate esterase, paraoxonase, aspirin esterase and red blood cell esterase), albumin and anthropometric indices (weight, triceps skinfold thickness and mid arm circumference) were made before the study and repeated at week 4 and 8. 4. There was a significant increase in plasma cholinesterase at week 4 (P < 0.05) but this was not statistically significant at week 8. There were no significant changes in any of the other esterase activities or anthropometric measurements. 5. We conclude that the lower esterase activities of the frail chronically hospitalised elderly do not respond to dietary supplementation for a period of 8 weeks with routinely available products. The hypothesis that lower esterase activities are the direct result of undernutrition which would be corrected by dietary supplementation has not been supported by this study.

Aged↗
PubMed1992

Molecular cloning of a gene involved in methotrexate uptake by DNA-mediated gene transfer.

A methotrexate-resistant Chinese hamster ovary cell line deficient in methotrexate uptake has been complemented to methotrexate sensitivity by transfection with DNA isolated from a wild-type Chinese hamster ovary genomic cosmid library. Primary and secondary transfectants, which contain a limited number of cosmid sequences, have been shown to regain methotrexate sensitivity and to take up methotrexate. Furthermore, the DNA from three cosmid clones, isolated from a primary methotrexate-sensitive transfectant, after transfection rescued the methotrexate-resistant phenotype at a high frequency. Restriction endonuclease analysis of the DNA of these cosmid clones indicated that they overlapped extensively and shared two regions of Chinese hamster ovary DNA of 6.6 kb and 20.6 kb. These observations indicate that a gene involved in methotrexate uptake is contained in its entirety within one of these regions. This is the first report of the functional molecular cloning of a gene involved in methotrexate uptake. A general strategy is also described for screening large cosmid libraries from primary transfectants.

Animals↗
PubMed1992

Interactions of plant zinc and plant species on the bioavailability of plant cadmium to Japanese quail fed lettuce and spinach.

Many cadmium-contaminated environments contain high levels of zinc. The effects of plant Zn and plant species on plant Cd bioavailability were tested in Japanese quail fed lettuce and spinach. Four groups of birds received 10% of their diets as lettuce or spinach leaves intrinsically labeled with 109Cd and containing low or high intrinsic Zn. Two other groups were fed control diets containing 109Cd as CdSO4 and low or high Zn as ZnCO3. Cadmium concentrations in diets ranged from 0.857 to 1.05 micrograms/g dry wt. Zinc concentrations in low-Zn diets ranged from 21.2 to 22.8, and in high-Zn diets from 56.0 to 63.3 micrograms/g dry wt. Increased lettuce and spinach Zn decreased plant Cd retention in kidney, liver, and jejunum-ileum of Japanese quail. Spinach Cd was less absorbed than lettuce Cd at both Zn levels. Inorganic Zn produced a lesser decrease in Cd retention in kidney, liver, and jejunum-ileum than did plant Zn. We conclude that (1) crops that transport Zn and Cd readily into edible tissues show lower Cd bioavailability when grown in Zn-Cd contaminated environments than in Cd-only polluted sites, (2) plant species differ in Cd bioavailability for identical concentrations of Zn and Cd in edible tissues, and (3) toxicological studies with animals exposed to Cd salts and Zn supplements do not assess Cd bioavailability of Zn-Cd contaminated crops.

Absorption↗
PubMed1992

Whole body heat stress fails to limit infarct size in the reperfused rabbit heart.

OBJECTIVE: It has recently been shown that induction of heat stress proteins by whole body heat stress confers myocardial protection in the isolated in vitro rat and rabbit heart. This study extends the above studies by examining the effects of stress protein synthesis on the limitation of infarct size in the in vivo rabbit heart model. METHODS: 30 male New Zealand white rabbits were used. Six rabbits were used for measurement of heat stress protein; 10 were used for infarct size determination in a heat stress group (HS); 14 were used for infarct size determination in a control group. There were 10 exclusions. Under anaesthesia, body temperature was raised to 42 degrees C for 15 min in the HS group. Following 24 hours of recovery rabbits were reanaesthetised and the hearts subjected to a 45 min period of regional ischaemia followed by 3 h reperfusion. The risk zone was defined with fluorescent particles and the infarct area determined by tetrazolium staining. Western blotting showed an increase in the 72 KD heat stress protein in hearts in the HS group. RESULTS: Infarct size as a percent of risk area was 61.4 (SEM 6.4)% (n = 14) in control hearts and 71.8(7.3)% (n = 10) in the HS hearts. These results were not statistically significant. CONCLUSIONS: No protective effect of heat stress could be seen when infarct size was used as the end point. Either the protection seen in earlier studies using the Krebs perfused isolated heart model does not accurately reflect protection against myocardial infarction, or heat stress itself may induce injurious factors in the blood which will negate any direct protective effect to the myocardium in this model.

Animals↗
PubMed1992

Interindividual variations in enzymes controlling organophosphate toxicity in man.

1 Interindividual variations in an unexposed population have been defined for five enzymes involved in organophosphate (OP) toxicity. The enzymes measured were: red blood cell acetylcholinesterase (AChE), lymphocyte neuropathy target esterase (NTE), serum cholinesterase (ChE), serum paraoxonase and serum arylesterase. 2 AChE and arylesterase were normally distributed in the population whilst the distribution of NTE, ChE and paraoxonase deviated significantly from normal. 3 Assay precision and intra-individual variability were measured for each of the enzymes; the effect on interindividual variation was assessed. 4 Variations in enzyme activities between individuals could have profound effects on susceptibility to OP toxicity. Prior determination of these enzymes may be predictive of susceptibility. 5 Lymphocyte NTE has some limitations as an indicator of exposure to neurotoxic OPs.

Acetylcholinesterase↗
PubMed1991

Esterase activity in rat hepatocytes.

Hydrolysis of acetylsalicylate, benorylate, phenetsal, fluazifop butyl and paraoxon has been studied with freshly isolated rat hepatocytes maintained as a monolayer. Acetylsalicylate and paraoxon were the poorest substrates for hydrolysis whereas benorylate was hydrolysed one hundred times faster. Phenetsal and fluazifop butyl were both hydrolysed at one-tenth of the rate of benorylate. Inhibitor studies with paraoxon, BNPP and physostigmine indicated the involvement of different carboxylesterase isozymes. Studies with acetylsalicylate indicated that uptake of the substrate into the hepatocyte may influence the rate of formation of the hydrolysis product. Studies of hydrolysis in hepatocytes more closely reflect in vivo hepatic hydrolysis than subcellular fractions as cytosolic and microsomal esterases can act in parallel.

Animals↗
PubMed1991

Fate of carbaryl in rat skin.

Metabolism of carbaryl by rat liver and skin post-mitochondrial fraction has been measured in the presence and absence of cofactors to promote different metabolic pathways. The metabolic capacity was compared with the metabolism of carbaryl during percutaneous absorption in a static skin diffusion system using a variety of receptor fluids. Carbaryl was metabolised by hydrolysis, and ring hydroxylation followed by conjugation to the glucuronide or sulphate with liver post-mitochondrial fraction. Using skin post-mitochondrial fraction only hydrolysis and conjugation were detected. No metabolism was seen during percutaneous absorption in vitro even with receptor fluids which maintain the skin tissue viability. Studies using post-mitochondrial fraction indicate the metabolic capacity of the tissue, whereas during absorption, rates of absorption and accessibility of substrate to the metabolising enzymes must be considered.

Animals↗
PubMed1991

Percutaneous absorption and metabolism of aldrin by rat skin in diffusion cells.

Using a static diffusion cell with varying receptor fluids the viability of isolated rat skin mounted as whole skin or as split thickness skin has been studied. Skin viability decreased with time with phosphate buffer or Eagles MEM and was not supported with ethanol/water as the receptor fluid. The pesticide aldrin was absorbed through the skin into ethanol/water but not the aqueous receptor fluids. With viable skin preparations aldrin was metabolised to dieldrin and absorbed aldrin and the metabolite remained in the skin. Viable skin preparations must be used to assess in vitro, the degree of metabolism of xenobiotics which occurs during percutaneous absorption.

Aldrin↗
PubMed1991

Metabolism of aldrin to dieldrin by rat skin following topical application.

Metabolism of the pesticide aldrin to dieldrin in the rat was studied following topical and ip administration of 0.1-10 mg aldrin/kg body weight. When aldrin was applied topically to the dorsal skin at a dose of 10 mg/kg body weight, absorption was less efficient than after ip administration; lower blood levels of aldrin and dieldrin were seen and peak dieldrin levels were delayed. After ip administration of 1 or 10 mg aldrin/kg body weight, dieldrin was found at similar concentrations in the dorsal and ventral skin 7 hr later, whereas 7 hr after topical administration of 10 mg aldrin/kg, the dieldrin concentration in the skin at the dorsal site of application was four times higher than that at a ventral skin site. Similar differences in dieldrin concentrations between dorsal and ventral skin persisted throughout the 7-hr period following topical application. The results indicate that topically applied aldrin is metabolized to dieldrin in the skin during absorption, but the overall proportion of metabolism that takes place in the skin is small compared with the contribution of the liver. Dieldrin was not detected in the ventral skin remote from the application site 1 hr after topical application of aldrin, whereas a dieldrin concentration of 2.2 nmol/g was detected in the skin of the application site at this time; more than 99% of this dieldrin was probably formed locally by dermal metabolism of percutaneously absorbed aldrin. The efficiency of conversion of applied aldrin to dieldrin decreased with increasing aldrin dose in the range 0.1 to 10 mg/kg.

Administration, Topical↗
PubMed1991

The accumulation of 111In-eosinophils induced by inflammatory mediators, in vivo.

Eosinophils are implicated in the pathogenesis of a variety of allergic inflammatory diseases such as asthma. Several substances have been shown to be chemotactic for eosinophils in vitro, but the inflammatory mediators involved in the accumulation of eosinophils in vivo are as yet unidentified. In this study we have developed a system to measure the accumulation of 111In-eosinophils in guinea-pig skin in vivo. Horse serum-induced guinea-pig peritoneal eosinophils were radiolabelled with 111In and injected intravenously into recipient animals. 125I-albumin was also injected intravenously in order to measure local oedema formation simultaneously. A range of putative mediators was injected intradermally and responses measured for up to 2 hr. Of the mediators tested, guinea-pig C5a des Arg in zymosan-activated plasma was the most active. Recombinant human C5a (rHC5a) was also highly active, but less than the guinea-pig material. C5a des Arg in maximally activated plasma induced a 1500% increase in eosinophil accumulation, while rHC5a (10(-10) mol dose) induced a 600% increase. Platelet-activating factor (PAF) and leukotriene B4 (LTB4) were also tested for comparison. With respect to 111In-eosinophil accumulation, the order of potency of the mediators tested was as follows: guinea-pig C5a des Arg greater than LTB4 greater than PAF. In contrast, the order of potency of the mediators with respect to oedema formation was: PAF greater than guinea-pig C5a des Arg greater than LTB4. The techniques described will facilitate analysis of the mechanisms involved in eosinophil accumulation in defined inflammatory reactions.

Albumins↗
PubMed1990

The metabolic effects of aspirin in fasting and fed subjects: relevance to the aetiology of Reye's syndrome.

As a possible model for the mechanism of precipitation of Reye's Syndrome in children the metabolic effects of oral aspirin were studied in normal subjects in the fasted and fed states, to determine whether aspirin altered fatty acid oxidation. Starvation increased blood 3-hydroxybutyrate concentrations, but aspirin had no effect on this or other metabolite concentrations in either the fasted or fed states.

3-Hydroxybutyric Acid↗