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Biomedical subjects

S Murray

Publications and source records attributed to S Murray.

At least 19 recordsLinked to original sources
PubMed1992

Intra- and interindividual variability in systemic exposure in humans to 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and 2-amino-1-methyl- 6-phenylimidazo[4,5-b]pyridine, carcinogens present in cooked beef.

During the cooking of beef, the genotoxic heterocyclic aromatic amines 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are formed. Little is known about the fate of these compounds in humans or the factors affecting it. We have developed assays based on capillary column gas chromatography-negative ion mass spectrometry capable of the simultaneous measurement of MeIQx, DiMeIQx, and PhIP in cooked meat and in human urine using stable isotope labeled analogues. Ten normal, healthy male volunteers were invited to consume a standard cooked meat meal (400-450 g lean beef, cooked as patties on a griddle hotplate) on four separate occasions over a period of 14 months. Following consumption of the test meals, urine was collected from 0 to 8 h, during which time all free amines were excreted and analyzed for MeIQx, DiMeIQx, and PhIP. Subjects ingested 240 +/- 9 (SEM) g cooked meat, which contained 2.2 +/- 0.2 ng MeIQx/g meat, 0.7 +/- 0.1 ng DiMeIQx/g meat, and 16.4 +/- 2.1 ng PhIP/g meat. The variability in relative systemic bioavailability was assessed from the percentage of ingested amine excreted unchanged in the urine. Subjects excreted 2.1 +/- 1.1% of MeIQx and 1.1 +/- 0.5% of PhIP ingested as unchanged amine in the urine. Levels of DiMeIQx in urine, if present, were below the sensitivity of our assay (20 pg/ml) and could not be detected in any of the samples analyzed. Irrespective of dose, urinary excretion of unchanged MeIQx or PhIP (expressed as a percentage of the ingested dose) remained constant for each individual subject. The intraindividual coefficients of variation for MeIQx (28.4%) and PhIP (23.7%) were low and the pooled interday (intrasubject) coefficients of variation for both compounds were only 19 and 3.4%, respectively. In contrast, inter-subject (intraday) variation was greater, with pooled coefficients of variation of 145% for MeIQx and 71% for PhIP. Based on these studies, it should be possible to use the percentage excretion of MeIQx and PhIP to assess the relative bioavailability of these compounds in humans.

Adult↗
PubMed1991

Identification of a functionally conserved surface region of rat cytochromes P450IA.

A region of rat cytochrome P450IA1 at residues 294-301 (Gln-Asp-Arg-Arg-Leu-Asp-Glu-Asn), equivalent to a proinhibitory region of cytochrome P450IA2, was identified by sequence alignment. Anti-peptide antibodies were successfully raised when the peptide was coupled through either its N- or its C-terminus to carrier protein, but no antibodies were produced against the so-called multiple peptide antigen, which consisted of eight copies of the peptide attached through its C-terminus to a synthetic base. Both of the anti-peptide antibodies bound specifically to cytochrome P450IA1 in the rat, as shown by e.l.i.s.a. and immunoblotting. They inhibited microsomal aryl hydrocarbon hydroxylase activity and the mutagenic activation of 2-acetylaminofluorene (these reactions are catalysed by cytochrome P450IA1), but not high-affinity phenacetin O-de-ethylation activity, which is catalysed by cytochrome P450IA2. However, there was differences in the properties of the two antisera in their binding to cytochromes P450IA1 in species other than the rat, their relative binding to the multiple peptide antigen, the yield of antibody following affinity purification using peptide coupled through its N-terminus to CNBr-activated Sepharose, and the binding of the purified preparations to N- and C-terminal-coupled peptide conjugates. These observations indicated that the antibodies were directed to the region of the peptide opposite to the end which was coupled to the carrier protein. Nevertheless, both of the antibody preparations bound equally well to the target cytochrome P450, thus indicating that, in the native protein, the whole of the peptide region is exposed on the surface of cytochrome P450IA1 and is available for binding by the antibodies. The role of this region appears to be the same in both cytochromes P450IA1 and P450IA2, despite the difference in its primary structure in the two cytochromes P450.

Amino Acid Sequence↗
PubMed1991

Combined assay for phenacetin and paracetamol in plasma using capillary column gas chromatography-negative-ion mass spectrometry.

A gas chromatographic-mass spectrometric assay has been developed for the measurement of phenacetin and its major metabolite paracetamol in plasma. Phenacetin and unconjugated paracetamol are analysed in a single chromatographic run while total paracetamol is measured separately after enzymatic hydrolysis. The two compounds, and the deuterated analogues used as internal standards, are analysed as their trifluoroacetyl derivatives and the mass spectrometer is operated in the electron-capture negative-ion chemical ionisation mode. The negative-ion mass spectra of the derivatives contain fragment ions, formed by loss of an acetyl group from the respective molecular ions, which are the base peaks in the spectra. When these ions are specifically monitored, amounts of derivative equivalent to 1 pg of parent compound can be detected. This allowed the development of an assay for phenacetin, unconjugated paracetamol and total paracetamol in plasma having a precision of 2.6, 1.4 and 2.4%, respectively, and preliminary results for a subject given a 100-mg oral dose of phenacetin are reported.

Acetaminophen↗
PubMed1991

Gas chromatographic-mass spectrometric assay to measure urinary N tau-methylhistamine excretion in man.

An assay has been developed for N tau-methylhistamine, a major metabolite of the autocoid histamine, based on gas chromatography-electron-capture negative-ion chemical ionisation mass spectrometry. N tau-Methylhistamine was extracted from urine by cation-exchange chromatography and converted to its di-(3,5-bistrifluoromethylbenzoyl) derivative. The latter has good chromatographic properties and gives a negative-ion mass spectrum with the molecular ion (M., m/z 605) as base peak. A commercially available trideuterated analogue of N tau-methylhistamine was used as internal standard. Basal urinary excretion of N tau-methylhistamine in five normal subjects was found to be 0.21 +/- 0.05 mumol/h (289 +/- 74 mumol/mol of creatinine). This value was not significantly altered in these subjects following the infusion of a subpharmacological dose of histamine. In eight atopic volunteers, basal urinary excretion of N tau-methylhistamine was also not significantly changed following challenge with inhaled allergen.

Adult↗
PubMed1991

The measurement of MeIQx adducts with mouse haemoglobin in vitro and in vivo: implications for human dosimetry.

We have investigated covalent binding of radiolabelled [14C]2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) to mouse haemoglobin in vitro and in vivo. Furthermore, we report the development of a capillary column gas chromatography negative ion mass spectrometry (GC-MS) assay capable of detecting MeIQx liberated from haemoglobin after acid or base hydrolysis. Following microsomal activation, the amount of radiolabelled material associated with haemoglobin in vitro increased with incubation time to 0.67 +/- 0.15 nmol/mg haemoglobin at 2 h (initial concentration 0.47 mM [14C]MeIQx, mean +/- SD, n = 6). Hydrolysis of these samples with acid revealed that 47-60% of the radiolabelled material covalently bound to haemoglobin was acid labile. Of this, 7.2-9.8% was recovered as MeIQx as determined by GC-MS. This liberated fraction should reflect the amount of sulphinic acid amide present which is formed when N-hydroxy-MeIQx reacts with sulphydryl-containing amino acids present in haemoglobin. In vivo, no radiolabelled material bound to haemoglobin could be detected in animals treated with the lowest dose of MeIQx (0.2 mg/kg). At higher doses, there was a dose-dependent increase in the covalent binding of radiolabel to haemoglobin (2.0-200 mg/kg). However, the GC-MS assay for hydrolysable adducts of MeIQx yielded detectable quantities of MeIQx (32.2 +/- 17.5 fmol MeIQx/mg haemoglobin) only at the highest dose used. Application of the GC-MS assay to human haemoglobin samples showed that acid-labile adducts of MeIQx, if present, were below the limit of detection of the assay. These results show that levels of sulphinamide adducts of the dietary aromatic amine MeIQx, with haemoglobin, are very low and the implications for future human dosimetry of this carcinogen are discussed.

Animals↗
PubMed1991

Epidemiology of sharps accidents in general surgery.

A prospective study was carried out of all general surgical operations in one theatre of a teaching hospital over a 6-week period to identify the predisposing factors involved in the occurrence of sharps accidents and their relative importance. Although various predisposing factors have been intimated, the relative importance has never been ascertained. Glove puncture was used as an objective measure of a sharps accident and this was compared with subjective reporting of needlestick injury. The overall rate of sharps accidents per surgeon per operation was 23%. The position at the operating table and medical rank of operator affected the rate of accidents more than duration of operation. The group at most risk of sharps accidents was junior surgeons acting as the principal operator. It is important to recommend inoculation against hepatitis B in this group before starting surgical training. Another method of minimizing the risk to junior surgeons would be compulsory training on surgical rigs. Operations on patients with AIDS or hepatitis B should be carried out by the most senior surgeon available to reduce the risk of sharps injury and disease transmission.

Accidents, Occupational↗
PubMed1991

Needlestick injury in surgeons: what is the incidence?

A prospective study by questionnaire was carried out to investigate the incidence of needlestick injury in the operating theatre staff of a teaching hospital and to calculate the individual risk of acquiring blood-borne virus infection in the UK from this source. The individual rate of needlestick injury in operating theatre staff was 1.55% per surgeon per operation (confidence interval (Cl) 0.6-2.5%). The calculated rate of clinical hepatitis B in surgeons compared with the observed rate suggests that needlestick in theatre is the main mode of transmission.

Accidents, Occupational↗
PubMed1990

Histologic comparison of the pulsed dye laser and copper vapor laser effects on pig skin.

Albino pig skin was exposed to the copper vapor (CVL) and flash-lamp pulsed dye (PDL) lasers at 578 nm with a 3 mm diameter spotsize over a range of fluences until purpura and whitening were first established. The total irradiation time was the parameter that was varied in order for the CVL to reach the desired fluence. The lowest fluence producing each clinical endpoint was designated the threshold fluence: 34 J/cm2 was required to produce purpura using the CVL compared to 7.5 J/cm2 with the PDL laser. Histologically, skin exposed to purpura fluences from the CVL revealed the presence of constricted, disrupted papillary dermal blood vessels with trapped RBC's within them which were unlike those exposed to PDL where the irradiated vessels were dilated and packed with masses of intravascular agglutinated RBC's. The whitening threshold fluences for the CVL and PDL lasers were 67 J/cm2 and 29 J/cm2, respectively. Streaming of epidermal cells and dermal collagen denaturation were observed in CVL irradiated skin, compared to occasional dyskeratotic epidermal cells and focal dermal collagen denaturation following PDL exposure. The mechanisms responsible for the clinical and histologic changes produced by the two laser systems are discussed.

Animals↗
PubMed1990

Assay of caffeine metabolism in vitro by human liver microsomes using radio-high-performance liquid chromatography.

The low turnover of caffeine in vitro by human liver microsomes makes the study of the metabolic pathways of this compound difficult. Analytical methods with high sensitivity and specificity are needed for the detection of its metabolic products. A method based on the on-line radiometric determination of [8C-3H]caffeine and its principal metabolite (paraxanthine) in man has been developed using reversed-phase high-performance liquid chromatography. The method has been successfully employed in preliminary studies of the kinetics of this reaction.

Biotransformation↗
PubMed1990

Debrisoquine oxidation phenotype and susceptibility to lung cancer.

1. It has been suggested that poor metabolisers of debrisoquine are at reduced risk of developing lung cancer from smoking cigarettes. This has been investigated in 82 patients with established cancer of the lung. 2. The frequency of poor metaboliser subjects was not different from that in the normal population. 3. There was no tendency for subjects with lung cancer to metabolise debrisoquine more rapidly than non-cancer subjects. 4. It is concluded that debrisoquine metabolic phenotype is not a good predictor of risk of developing lung cancer in the population at large.

Adenocarcinoma↗