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M Murray

Publications and source records attributed to M Murray.

At least 361 records · Page 20Linked to original sources
PubMed1988

Identification of the hepatic cytochrome P-450 isozymes induced and decreased by picloram.

Microsomes from male rats treated with picloram (100 mg/kg/day) for 7 days showed a 48% decrease in 16 alpha-hydroxylase activity when incubated with (4-14C) androstenedione. These data are consistent with the assertion that picloram decreases the titer of hepatic male specific cytochrome P-450h. Several lines of evidence suggested that picloram is an inducer of hepatic cytochrome P-450 in male rats. First, SDS polyacrylamide gel electrophoresis revealed an intensified hepatic microsomal polypeptide (MW 54,000) following picloram pretreatment. This polypeptide co-migrated with protein bands which were correspondingly intensified after pretreatment with known inducers of cytochrome P-450d (3-methylcholanthrene and isosafrole). Second, no increase in the binding of metyrapone to picloram treated microsomes was noted compared with controls, suggesting no increase in phenobarbital-inducible forms of cytochrome P-450. Third, hepatic microsomes from picloram treated rats activated 2-amino-3-methylimidazo [4,5-f] quinoline (a cytochrome P-450d mediated catalysis) causing a 5-fold increase in the number of induced Salmonella typhimurium TA98 revertant colonies formed compared with control microsomes. Fourth, the binding of n-octylamine to hepatic microsomes from picloram-treated rats showed, like microsomes from 3-methylcholanthrene-treated rats, an increase in the proportion of high-spin cytochrome P-450 present. Cytochrome P-450d is known to be a high spin haemoprotein.

Androstenedione↗
PubMed1988

Comparative effects of antithrombitic and antimycotic N-substituted imidazoles on rat hepatic microsomal steroid and xenobiotic hydroxylases in vitro.

N-Substituted imidazoles have been shown to be potent inhibitors of microsomal mixed-function oxidase activities in vitro and in vivo. In the present study the effects of two antithrombitic (dazmegrel and dazoxiben) and four antimycotic (ketoconazole, econazole, miconazole and clotrimazole) imidazoles on microsomal cytochrome P-450-mediated steroid and xenobiotic hydroxylases were studied in vitro. Despite the presence of the N-substituted imidazole moiety, the antithrombitic agents were essentially non-potent as inhibitors of all of the oxidase activities evaluated. In contrast, the antimycotic drugs were potent inhibitory compounds. Binding studies revealed that all six imidazoles elicited type II optical difference spectra and exhibited relatively high affinity for ferricytochrome P-450 in microsomal suspensions (Ks range 0.26-0.73 microM for the antimycotic agents and 6.5 microM and 21 microM for dazmegrel and dazoxiben, respectively). The structural feature that the antithrombitic compounds share is a carboxylate function so that, at physiological pH, less than 1% of the drug would be present in the unionised form. This functionality is absent from the structures of the antimycotic agents which possess much greater hydrophobic character. Even though the antithrombitic imidazoles elicit type II binding interactions of quite high affinity it would appear from this study that significant inhibition potency does not necessarily follow. The present findings also suggest that interesting differences exist between the active site binding regions in the cytochrome P-450 that catalyse thromboxane synthetase activity and those involved in microsomal drug oxidation. Inhibitor hydrophobicity is clearly an important factor in the inhibition of microsomal cytochromes P-450 whereas effective thromboxane synthetase inhibitors may be quite hydrophilic at physiological pH.

Animals↗
PubMed1988

In situ hybridization of mRNA for beta-preprotachykinin and preprosomatostatin in adult rat dorsal root ganglia: comparison with immunocytochemical localization.

In situ hybridization histochemistry was used to identify neurons in rat dorsal root ganglia that contained mRNAs encoding beta-preprotachykinin and preprosomatostatin. The distribution of these neurons was compared with the distribution of neurons containing tachykinins or somatostatin, identified using immunocytochemical techniques. Neurons labelled for beta-preprotachykinin mRNA constituted 20% of the total neuronal population and belonged to the small cell class. Neurons labelled for preprosomatostatin mRNA with either RNA or DNA hybridization probes constituted approximately 10% of the total cells and comprised a small cell group that differed in average size from the beta-preprotachykinin labelled population. The distribution of cells containing tachykinin- or somatostatin-like immunoreactive material was identical to the distribution of cells containing the respective mRNAs and, in addition, individual somata in adjacent sections contained both the mRNA precursor and the peptide. These results suggest that for these neuropeptides the sensitivity of the two methods is equivalent and the respective mRNAs and peptides are co-localized in the same neurons.

Animals↗
PubMed1988

Hepatic microsomal metabolism of androst-4-ene-3,17-dione: relative importance of ring hydroxylation and aromatization in control and induced rat liver.

The purpose of these studies was to determine whether oestrogen production is a quantitatively important pathway in the hepatic microsomal metabolism of androst-4-ene-3,17-dione. The effects of the enzyme inducing agents phenobarbitone and beta-naphthoflavone on microsomal cytochrome P-450-mediated androst-4-ene-3,17-dione hydroxylation and aromatization was investigated in the rat in vitro. In microsomal fractions from untreated rats the ratio of hydroxylated products to aromatized (oestrogenic) metabolites was 33:1. Phenobarbitone pretreatment of rats increased total hydroxylation by about 20% but did not change the ratio of hydroxylated to aromatized products (27:1). In contrast, beta-naphthoflavone induction decreased total hydroxylation to about 35% of control but did not affect total aromatization. Thus the ratio of hydroxylation to aromatization was significantly lower than in control microsomes (17:1). The principal aromatized products were oestriol and 2-hydroxyoestradiol-17 beta, with oestradiol-17 beta and its 4-hydroxy metabolite as minor products; no oestrone was observed. In further studies of the microsomal metabolism of oestrone, the major product was oestradiol-17 beta whereas hydroxylated metabolites were only minor products. Oestradiol-17 beta, in contrast, was hydroxylated to a considerable extent. These findings suggest that oestrone is a better substrate for the microsomal 17 beta-oxidoreductase than it is for cytochrome P-450. It therefore appears likely that any oestrone formed from the aromatization of androst-4-ene-3,17-dione would be readily converted to oestradiol-17 beta which, in turn, is subject to cytochrome P-450-mediated hydroxylation. Although the liver is a site of C19-steroid aromatization, it appears unlikely that this organ could contribute significantly to serum oestrogen levels since microsomal hydroxylases are readily able to convert aromatized products to biologically inactive metabolites.

Androstenedione↗
PubMed1988

Factors influencing the duration of isometamidium chloride (Samorin) prophylaxis against experimental challenge with metacyclic forms of Trypanosoma congolense.

The duration of a single isometamidium chloride (Samorin) prophylactic treatment against Trypanosoma congolense ILNat. 3.1 and T. congolense IL 285 was examined in 24 Boran steers with regard to (1) the dose of drug, (2) the level of metacyclic challenge and (3) the influence of infection with an unrelated serodeme at the time of treatment. The cattle were repeatedly challenged at monthly intervals between 2 and 7 months following treatment, either by five infected Glossina morsitans centralis or by intradermal inoculation of 5 X 10(3) or 5 X 10(5) in vitro-derived metacyclic trypanosomes. A dose of 1 mg kg-1 afforded complete protection for 4 months and 0.5 mg kg-1 for 3 months against the two T. congolense serodemes examined, irrespective of the method or weight of challenge. In another group of cattle, which had an established infection at the time of treatment, the duration of chemoprophylaxis against an unrelated serodeme was the same as the other groups which had no previous experience of trypanosome infection. Antibodies to metacyclics did not appear in any of the cattle as long as the chemoprophylaxis was effective. An exception to this was the group challenged with 5 X 10(5) in vitro-derived metacyclic parasites, in which low antibody titres were detected. In all cases these proved to be non-protective. It was concluded that, under the experimental conditions employed, (1) there was a direct relationship between drug dosage and the duration of chemoprophylaxis, (2) the weight of metacyclic challenge did not affect the duration of chemoprophylaxis and (3) when used to treat an existing infection, isometamidium chloride exerted the same degree of chemoprophylactic activity.

Animals↗
PubMed1988

Evidence for dopaminergic and opioid involvement in the regulation of locomotor activity in the land crab Gecarcinus lateralis.

1. Computerized analysis of the crabs locomotor behavior revealed an initial increase in activity followed by a gradual decrease over a 12 min observation period. 2. Dopamine, in a dose-dependent manner, inhibits locomotor activity. The effect can be antagonized with the dopamine antagonist, haloperidol. This suggests that dopaminergic influences are involved with locomotor mechanisms. 3. FK 33,824, a stable opioid analog, significantly enhances the initial excitatory locomotor activity. Naloxone, a potent opiate antagonist, can block the excitatory action induced by FK 33 824. This suggests the presence of an opioid modulation mechanism in the regulation of locomotor activity. 4. Concomitant administration of the various agents results in the behavioral characteristics of the agonist appearing when the appropriate antagonist is not present. Thus, administration of dopamine + FK 33,824 + haloperidol results in enhanced locomotor activity. 5. Concomitant dopamine and FK 33,824 administration results in enhanced locomotor activity. This suggests that the opioid mechanism is closer to the last step in affecting the organism's locomotion or in initiating activity.

Animals↗
PubMed1988

Extravascular foci of Trypanosoma vivax in goats: the central nervous system and aqueous humor of the eye as potential sources of relapse infections after chemotherapy.

Relapse of parasitaemia after drug treatment of trypanosome infection is normally attributed to drug-resistance on the part of the parasite, under-dosage of the drug or reinfection of the host. In addition, inaccessibility of parasites to drug through sequestration in privileged extravascular sites has been shown in the past to occur with Trypanosoma brucei, and we have obtained evidence that extravascular foci of T. vivax can also serve as a source of relapsing infections. Infection of goats with a West African stock of T. vivax resulted in severe illness, which was fatal if untreated. During the terminal stage of an acute infection, clinical signs of central nervous system involvement were apparent. Histologically, the choroid plexus was swollen and oedematous, and in some cases meningitis or meningoencephalitis was seen. Trypanosomes could be detected in the cerebrospinal fluid, and also extravascularly in the choroid plexus and meninges. In three cases they were present in the aqueous humor, associated with corneal cloudiness or opacity. Treatment of 2 goats with the trypanocidal drug diminazene aceturate eliminated parasitaemia, but infections in both relapsed about 6 weeks later, despite trypanosomes being undetectable in the bloodstream during the intervening period. We conclude that the relapse infections were caused by reemergence of trypanosomes from the CNS and/or the eye, where sequestered parasites may have been inaccessible to the trypanocide.

Animals↗
PubMed1988

Sex- and substrate-dependent changes in hepatic cytosolic glutathione S-transferase enzymes produced by dietary choline-deficiency.

The effect of 30 week intake of a choline-deficient (CD) diet on cytosolic glutathione S-transferase (GST) activity was investigated in rats of both sexes. GST activities in choline-supplemented (CS) control male cytosol were higher than those in CS-female cytosol for five test substrates--1-chloro-2, 4-dinitrobenzene (CDNB), 1,2-epoxy-3-(p-nitrophenoxy)-propane, trans-4-phenyl-3-buten-2-one, p-nitrobenzyl chloride (PNBC) and 1,2-dichloro-4-nitrobenzene (DCNB). The CD dietary regimen produced a relatively uniform decrease in GST activities in male liver to 37-59% of CS-control. With the exception of CDNB conjugation, GST activities in CD-male and CS-female cytosols were not significantly different. On the other hand, in female rats, the CD diet increased GST activity with PNBC and DCNB as substrates to 153 and 204% of respective CS-control female activities; other GSTs were unchanged. Hepatic cytosols from female rats were subfractionated on Whatman CM-52 and subjected to electrophoresis on polyacrylamide gels. The principal finding was that the relative concentration of GST subunit 3 (mol. wt approximately 27 kd) was apparently increased in CD-female rat cytosol; a finding that is consistent with the observed increase in DCNB- and PNBC-conjugation. Thus it is apparent that intake of the tumorigenic CD diet by male rats results in the feminization of GST activity, whereas in females GST subunit 3 is upregulated. The impaired regulation of these enzymes in CD-rats is an early event in relation to the development of hepatocellular carcinoma.

Animals↗
PubMed1988

Infective endocarditis: incidence and mortality in the North East Thames Region.

A survey of infective endocarditis in the North East Thames Regional Health Authority was carried out over a period of 30 months from 1982 to 1984. The incidence, clinical characteristics, and in-hospital mortality were studied. Important causes of endocarditis were dental treatment, the presence of dental disease, drug abuse, and cytoscopy. The omission or incorrect administration of antibiotic prophylaxis in patients with valve disease was noted, but failure of correctly prescribed antibiotic prophylaxis was not recorded. Adverse prognostic features were increased age, prosthetic valve infection, Gram negative or staphylococcal infections, and aortic valve involvement. In contrast, mortality was lower in patients with mitral valve prolapse, ventricular septal defect, and streptococcus viridans infection. Deaths were usually attributable to irreversible complications present at the time of diagnosis. Vegetations were detected on the echocardiogram in half of those studied and mortality was higher in those with vegetations than without. Operation for native valve infection was associated with a low mortality and it is likely that the overall mortality for infective endocarditis has been improved by surgical intervention.

Endocarditis, Bacterial↗
PubMed1988

The Hawthorne effect in the measurement of adolescent smoking.

It is possible that the process of repeatedly measuring the smoking behaviour of adolescents may very well affect that behaviour. This paper reports a test for the extent of such a "Hawthorne" effect in a longitudinal survey of smoking by English adolescents. The self-reported smoking behaviour of 15-16 year olds who attended schools which had participated in the study for five years was compared with that of 15-16 year olds who attended other schools. The prevalence of smoking was lower in those schools which had been surveyed for five years. A number of possible explanations for this finding are discussed. It is concluded that such a "Hawthorne" effect is unlikely to bias analyses relying on comparisons within the data set. However, they can certainly bias the prevalance estimates obtained from such a study. Thus they provide yet another reason why prevalence estimates from cohorts studied over a period of time must be used with considerable caution.

Adolescent↗
PubMed1988

Verapamil-induced carbamazepine neurotoxicity. A report of two cases.

Two patients with signs of carbamazepine neurotoxicity after combined treatment with verapamil showed complete recovery after discontinuation of the calcium entry blocker. Use of verapamil in combination with carbamazepine should either be avoided or prescribed only with appropriate adjustment of the carbamazepine dose (usually reduction of the carbamazepine dose by one half).

Adult↗
PubMed1988

Source of raised serum estrogens in male rats with portal bypass.

We sought to establish the mechanism for the raised serum estrogen levels that occur in male rats with portal hypertension and resultant portal bypass. Using the portal vein ligated (PVL) rat model, we evaluated plasma steroid hormone concentrations, metabolic clearance rate (MCR) of estradiol, and hepatic metabolism of androstenedione to estrogens and other products. In contrast to serum testosterone levels that were reduced, serum androstenedione levels were normal in the PVL rat. Estradiol MCR was measured by a constant intravenous infusion technique and was found to be similar in PVL and control animals. Androstenedione MCR was determined during constant intravenous infusion of [3H]androstenedione, and the resultant radiolabeled steroids present in plasma were separated by thin layer chromatography. The MCR of androstenedione was not diminished in PVL rats compared with controls. However, there was a sevenfold increase in the plasma estradiol derived from [3H]androstenedione in rats with portal bypass. Examination of radiolabel excreted in bile during infusion of [3H]androstenedione showed that 25-46% of this steroid was converted to estradiol in PVL rats compared with less than 3% in control male rats (P less than 0.001). Moreover, there was a selective reduction in the excretion of 16 alpha-hydroxyandrostenedione, a finding which suggested that the metabolism of androstenedione via this pathway was decreased. Androstenedione 16 alpha-hydroxylation is known to be catalyzed by a male-specific cytochrome P-450 isoform, P-450UT-A. We conclude that raised plasma estradiol levels after portal bypass in male rats are due to increased production rates, resulting in turn from enhanced aromatization of androstenedione to estradiol. On the basis of the observed specific changes in androstenedione hydroxylation pathways, it is proposed that alterations in levels of sex-specific forms of cytochrome P-450 occur in male rats with portal bypass and could account for the enhanced formation of estradiol.

Androstenedione↗
PubMed1988

Anxiety and aspects of health behavior among adolescents in Northern Ireland.

A sample of 238 15- to 16-year-old secondary school students from Northern Ireland answered a questionnaire in their schools about the level of anxiety and some aspects of their health behavior. Analysis of the findings showed that these teenagers had no higher anxiety than a Northern American sample of teenagers. In addition, anxiety was clearly correlated with a variety of health complaints and with use of the health service. The findings are discussed with reference to previous research on adolescent health and on stress in Northern Ireland.

Adolescent↗