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Biomedical subjects

N M Wilson

Publications and source records attributed to N M Wilson.

At least 73 records · Page 4Linked to original sources
PubMed1987

Product inhibition of benzo[a]pyrene metabolism in uninduced rat liver microsomes: effect of diol epoxide formation.

Conversion of benzo[a]pyrene (BP) to BP 7,8-dihydrodiol 9,10-oxides (DE) (measured as 7,10/8,9-tetrols) by untreated (UT) rat liver microsomes is over 10 times slower than following 3-methylcholanthrene (MC) induction. Time courses have been subjected to a kinetic analysis analogous to that previously reported for metabolism by MC-induced microsomes (J. Biol. Chem., 259 (1984) 13770-13776). Competition between BP and 7,8-dihydrodiol for P-450 is the major determinant of the rate of DE formation. Glucuronidation of quinones and phenols only increases the isolated BP metabolites including DE by 40%. This indicates far less inhibition by these products than for metabolism in MC-microsomes (4-6-fold). Thus stimulation may result from a decreased quinone-mediated oxidation of metabolites. In the presence of DNA, UT-microsomes metabolize BP to approximately equal amounts of 9-phenol-4,5-oxide (9-PO) and DE/DNA adducts. Addition of uridine diphosphoglucuronic acid (UDPGA) fails to enhance modification of DNA by DE, but formation of the 9-PO adduct is reduced as a result of lower free 9-phenol levels. The kinetic characteristics of BP metabolism by UT-microsomes are highly sensitive to the presence of very small but variable amounts (2-25 pmol/mg) of the very active cytochrome P-450c, which is the predominant form in MC-microsomes. The major effect of elevated levels of P-450c is an 8-fold increase in DE formation at low concentrations of BP due to a lowering of Km (7.9-2.6 microM) and an increase in the regioselectivity for DE formation from 7,8-dihydrodiol (5-15% of total BP metabolites). The formation of DE was directly correlated with the content of P-450c (r = 0.94). The presence of increased levels of P-450c in UT-microsomes is probably due to previous exposure of the animals to environmental inducers and is minimized by controlled housing and feeding.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1987

Role of the oesophagus in asthma induced by the ingestion of ice and acid.

Twelve Asian patients with a history of asthma exacerbated by ingestion of ice and acidic drinks were selected for study. To determine the site of response to ingested ice and acid they were challenged with ice or dilute hydrochloric acid, which was orally retained on one day and swallowed on another. On a third day a placebo was given. The airway response was assessed by measuring FEV1 and the provocative concentration of histamine that reduced the FEV1 by at least 20% (PC20). There was no significant change in FEV1 or histamine PC20 after placebo or the orally retained challenges for the group as a whole or for any individual. After the ice and hydrochloric acid had been swallowed there was a small but statistically significant mean fall in FEV1, increasing to a maximum 90 minutes after ingestion, together with a significant increase in bronchial responsiveness. As conditioning of the inspired air would have been similar after orally retained and after swallowed ice or acid, the response is likely to be due to oesophageal stimulation. The mechanism of the response to oesophageal stimulation is unclear, but the slow time course seems to preclude a simple neural reflex.

Acids↗
PubMed1987

Duration of protection by oxitropium bromide against cholinergic challenge.

In order to determine the duration of action of the inhaled anticholinergic agent oxitropium bromide, a controlled study of the effect of pre-treatment with oxitropium bromide 200 micrograms against cholinergic challenge was carried out in ten asthmatic subjects (6 children, 4 adults). After baseline measurements of lung function (FEV1 and sGaw) and methacholine PC20 (the concentration of methacholine to produce a 20% fall in FEV1) oxitropium bromide or placebo were inhaled double-blind on 2 separate days. Lung function and methacholine PC20 were then measured at 1, 3 and 6 h post dosing. Oxitropium bromide caused significant protection from methacholine challenge for 6 h (p less than 0.05).

Adolescent↗
PubMed1985

Food related asthma: a difference between two ethnic groups.

A survey of reported, food related asthma was carried out among children referred to hospital. Ninety nine replies were received from a postal questionnaire and 78 other children were interviewed personally. Both survey methods gave similar results. Symptoms from at least one item of diet were significantly more frequently reported by Asian than non-Asian children (91%:58% respectively). Ice, fizzy drinks, fried food, and nuts were incriminated significantly more often by the Asian children, but there was no difference in the prevalence of asthma associated with orange squash, milk, chocolate, or eggs. This ethnic difference could not be explained by a difference in severity of asthma. Results are presented of six Asian children who showed increased bronchial responsiveness after eating chips but not potato, thereby confirming their claim of asthma induced by fried foods. This report shows that food as a trigger of asthma is much more common than is generally accepted, particularly in Asian children.

Adolescent↗
PubMed1985

Gastro-oesophageal reflux and childhood asthma: the acid test.

The presence of gastro-oesophageal reflux was investigated in 18 children with moderate to severe asthma by overnight oesophageal pH monitoring. Appreciable reflux was found during sleep in eight; its relevance to nocturnal asthma was not clear. On another occasion the same children were challenged in a double blind fashion with a drink of dilute hydrochloric acid (0.001 N) and the response of the airways was monitored by peak flow measurements and by histamine challenge tests. There was a significant increase in mean histamine sensitivity (p = 0.001) 90 minutes after the acid drink without any associated change in baseline peak flow rate. Eight children had a significant response to the acid drink, and a further three reacted to a more concentrated solution (0.01 N). In those asthmatic children in whom reflux is associated with a positive response to an acid drink (five out of 18 in the present study) it seems likely that reflux exacerbates nocturnal symptoms.

Adolescent↗
PubMed1985

Increased bronchial responsiveness caused by ingestion of ice.

We studied 7 asthmatics who had a history of symptoms exacerbated by ice-cold drinks. Bronchial responsiveness to inhaled histamine was measured before and after ingestion of 40 ml of ice or water at room temperature. Although there was no change in baseline peak flow, a significant increase in bronchial responsiveness to histamine developed by 90 min after the ingestion of ice. No satisfactory explanation could be found.

Adolescent↗
PubMed1984

Hepatic mitochondrial cytochrome P-450 system. Distinctive features of cytochrome P-450 involved in the activation of aflatoxin B1 and benzo(a)pyrene.

Rat liver mitoplasts containing less than 1% microsomal contamination contain cytochrome P-450 at 25% of the microsomal level and retain the capacity for monooxygenase activation of structurally different carcinogens such as aflatoxin B1 (AFB1), benzo(a)pyrene (BaP), and dimethylnitrosamine. Both phenobarbital (PB) and 3-methylcholanthrene (3-MC) induce the level of mitochondrial cytochrome P-450 by 2.0- to 2.5-fold above the level of control mitoplasts. The enzyme activities for AFB1 (3-fold) and BaP (16-fold) metabolism were selectively induced by PB and 3-MC, respectively. Furthermore, the metabolism of AFB1 and BaP by intact mitochondria was supported by Krebs cycle substrates but not by NADPH. Both PB and 3-MC administration cause a shift in the CO difference spectrum of mitoplasts (control, 448 nm; PB, 451 nm; and 3-MC, 446 nm) suggesting that they induce two different forms of mitochondrial cytochromes P-450. Mitoplasts solubilized with cholate and fractionated with polyethylene glycol exhibit only marginal monooxygenase activities. The activity, however, was restored to preparations from both PB-induced and 3-MC-induced mitochondrial enzymes (AFB1 activation, ethylmorphine, and benzphetamine deamination and BaP metabolism) by addition of purified rat liver cytochrome P-450 reductase, and beef adrenodoxin and adrenodoxin reductase. The latter proteins failed to reconstitute activity to purified microsomal cytochromes P-450b and P-450c that were fully active with P-450 reductase. Monospecific rabbit antibodies against cytochrome P-450b and P-450c inhibited both P-450 reductase and adrenodoxin-supported activities to similar extents. Anti-P-450b and anti-P-450c provided Ouchterlony precipitin bands against PB- and 3-MC induced mitoplasts, respectively. We conclude that liver mitoplasts contain cytochrome P-450 that is closely similar to the corresponding microsomal cytochrome P-450 but can be distinguished by a capacity to interact with adrenodoxin. These inducible cytochromes P-450 are of mitochondrial origin since their levels in purified mitoplasts are over 10 times greater than can arise from the highest possible microsomal contamination.

Aflatoxin B1↗
PubMed1984

The role of secondary metabolism in the metabolic activation of 7,12-dimethylbenz[a]anthracene by rat liver microsomes.

The effect of induction by either phenobarbital (PB) or 3-methylcholanthrene (MC) on the kinetics of both primary and secondary metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) have been studied. PB and MC induction stimulate the initial rate of total DMBA metabolism 4- and 8-fold, respectively. Individual metabolites exhibited distinct time courses dependent on the inducer. With both induced and uninduced microsomes, formation of DMBA 5,6-dihydrodiol exhibited a 2-5 min time lag before reaching a maximum rate while, in contrast, formation of 7-hydroxymethyl-12-methylbenz[a]anthracene (7HOMMBA) declined substantially from linearity at a very early point in the reaction. This was most apparent after 2 min and total levels decreased after 5 min. Regioselectivity for both DMBA and 7HOMMBA were measured based on the initial rates of mono-oxygenation derived from these kinetics. In each set of microsomes, prior 7-hydroxylation redirected metabolism towards DMBA 3,4-dihydrodiol formation and away from 5,6-dihydrodiol. Large differences were noted for the effectiveness and regioselectivity of secondary metabolism via 7HOMMBA. MC-induced liver microsomes exhibited a stronger preference for secondary metabolism of 7HOMMBA than PB-induced and control microsomes. In all cases, 7HOMMBA dihydrodiols, formed from DMBA, appeared in the same ratio as when formed directly from 7HOMMBA, suggesting formation from 7HOMMBA rather than from 7-hydroxylation of primary dihydrodiols. The extent of secondary metabolism of primary products was calculated as the difference between the calculated formation (determined from the appropriate regioselectivity and DMBA disappearance) and the quantitated level at a particular reaction time. However, for MC-induced microsomes, quantitation of 7HOMMBA mono-oxygenated metabolites accounted for less than 50% of the calculated 7HOMMBA secondary metabolism. This discrepancy results from selective further oxidation of 7HOMMBA phenols. For control and PB-induced liver microsomes, quantitation of identifiable 7HOMMBA mono-oxygenated metabolites agreed well with calculated secondary 7HOMMBA metabolism. Based on the results presented here, factors that favor hydroxylation of PAH prior to bay-region diol-epoxide formation are discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

Binding and metabolism of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene by seven purified forms of cytochrome P-450.

Seven different forms of cytochrome P-450 have been purified from rat liver microsomes. The major 3-methylcholanthrene (MC) inducible cytochrome P-450 (form c) exhibits the greatest activity toward both benzo[a]pyrene (BP) (58 min-1) and 7,12-dimethylbenz[a]anthracene (DMBA) (29 min-1) and forms substantially high spin, high affinity complexes (Kd = 10 nM) with both hydrocarbons. Cytochrome P-450d, a minor MC-inducible form, has far lower activity for metabolism of both polycyclic aromatic hydrocarbons (PAH), yet also forms high affinity complexes (Kd approximately 100 nM) with both PAH, retaining the full high spin state of the free cytochrome. Although two phenobarbital (PB)-induced forms (P-450's b and e) differ by only 13 amino acids, they exhibit significant differences in metabolism of PAH and in complex formation. Whereas P-450b is only active in metabolism of DMBA (9.8 min-1 versus 1.9 min-1 for BP), P-450e has low activity for both substrates (3.3 and 1.2 min-1). Nevertheless, P-450e forms a high affinity complex (Kd approximately 100 nM) with both PAH that enhances the proportion of the high spin state (from 30% to 70%). Failure to displace n-octylamine (NOA) suggests binding that is removed from the heme. P-450b remains low spin in the presence of PAH and NOA is again not displaced. In addition, the two forms can be distinguished by their regioselectivities for both PAH. P-450's a, h, and pregnenolone-16 alpha-carbonitrile (PCN) exhibit little activity toward BP or DMBA, but P-450 PCN does form a low spin complex with BP (not DMBA). Regioselectivity in metabolism of DMBA by PB-induced microsomes does not agree with that of the major constituent forms. Only the minor, less active purified forms (e and a) mediate substantial 12-hydroxylation and 3,4-epoxidation of DMBA. Thus, additional factors in microsomal reactions must contribute to these differences.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Hyperventilation-induced asthma: evidence for two mechanisms.

The mechanism by which airway cooling induces airflow obstruction in asthmatic subjects has not yet been established. Using a pair of isocapnic hyperventilation challenges, with a 40-minute interval, we looked for the presence of a refractory period in 19 asthmatic patients (aged 9-18 years). The subjects fell into two groups. The eight in the "non-refractory" group showed less than a 25% reduction in response to the second challenge, but the 11 in the "refractory" group showed at least a 35% reduction. Twelve subjects also performed a hyperventilation challenge after cholinergic blockade with inhaled ipratropium bromide. In five, in whom no refractoriness after hyperventilation was seen, there was a significant protection from cholinergic blockade (p less than 0.05). In these a vagal (cholinergic) reflex seems likely. The remaining seven, who had a refractory period, received no significant protection from cholinergic blockade and therefore no evidence for the presence of any cholinergic mechanism. We conclude that two mechanisms are responsible for hyperventilation-induced asthma, one of which is a vagal reflex while mediator release may be the other.

Adolescent↗
PubMed1981

Glucose turnover and metabolic and hormonal changes in ethanol-induced hypoglycaemia.

Infusion of 67 g ethanol over four hours in fasted, non-obese normal men (a) induced hypoglycaemia by inhibiting gluconeogenesis; (b) produced noticeable increases in blood lactate, 3-hydroxybutyrate, and free fatty acid concentrations; (c) depressed plasma growth hormone concentrations, despite hypoglycaemia; and (d) raised plasma cortisol concentrations before significant hypoglycaemia occurred. These metabolic changes were explained by the reduction of redox state which accompanies ethanol oxidation. The pronounced changes in metabolic values recorded during this study suggested that the use of parenteral feeding regimens including ethanol needs to be reconsidered.

Blood Glucose↗
PubMed1981

Prazosin, an alpha 1-adrenoceptor antagonist, partially inhibits exercise-induced asthma.

The effect of prazosin, a potent and specific alpha 1-adrenoceptor antagonist given by inhalation (total nebulized 2 mg) was compared with placebo in a double-blind randomized study of 10 atopic asthmatic children. Prazosin significantly (p less than 0.01) reduced the severity of post-exercise bronchoconstriction (maximum fall in peak expiratory flow after exercise 21.4% +/- SEM 6.3% after prazosin compared with 42.5% +/- 7.3% after placebo). This protective action of prazosin suggests that activation of alpha 1-adrenoceptor may be involved in the pathogenesis of exercise-induced asthma either by facilitation of mast-cell mediator release or by direct contraction of bronchial smooth muscle. Prazosin did not significantly change resting bronchomotor tone or histamine-induced bronchoconstriction, suggesting no effect on bronchial smooth muscle contractility.

Adolescent↗
PubMed1981

A calcium antagonist, nifedipine, modifies exercise-induced asthma.

In eight extrinsic asthmatic subjects (age range 16-38 years) there was a significant reduction (p less than 0.01) in the severity of bronchoconstriction after a treadmill exercise test performed 30 minutes after nifedipine 20 mg sublingually. The maximum fall in peak expiratory flow after exercise was 36.0 +/- SEM 5.3% compared with a maximum fall of 56.5 +/- 4.1% after matched placebo capsules when given in double-blind randomised manner on separate days. There was no significant resting bronchodilation or change in blood pressure or heart rate after nifedipine. there was a significant rise in venous plasma histamine during exercise with placebo (6.1 +/- 0.8 to 13.5 +/- 3.5 nmol/l, p less than 0.01) but no significant increase with nifedipine (4.6 +/- 0.6 to 4.7 +/- 0.6 nmol/l) suggesting that nifedipine inhibits the release of mast cell mediators. The dose of inhaled histamine which provoked a 20% fall in peak expiratory flow was also significantly higher (p less than 0.05) with nifedipine (1.5 +/- 0.31 mg/ml) compared with placebo (2.7 +/- 0.63 mg/ml), indicating that there is a small inhibitory effect on bronchial smooth muscle contractility. Nifedipine is a potent antagonist of calcium ion influx in smooth muscle and secretory cells, and these studies suggest that it may inhibit release of mast cell mediators and reduce bronchial smooth muscle contractility in asthma.

Adolescent↗