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Biomedical subjects

G B Steventon

Publications and source records attributed to G B Steventon.

At least 19 recordsLinked to original sources
PubMed2005

Induction of cysteine dioxygenase activity by oral administration of cysteine analogues to the rat: implications for drug efficacy and safety.

One of the major steps in the oxidation of the sulphur-containing amino acid, L-cysteine, is the production of cysteine sulphinic acid, catalysed by the enzyme cysteine dioxygenase. This enzyme plays a key role in the intermediary metabolism of sulphur-containing compounds. The activity of this crucial enzyme is known to be influenced by sulphur-compound intake, being increased in animals fed an excess of L-cysteine or methionine. However, the affects on this enzyme of the chronic administration of drugs similar in structure to cysteine are unknown. This has now been investigated using the anti-rheumatic agent, D-penicillamine, and the mucoactive compound, S-carboxymethyl-L-cysteine. Repeated oral administration of these sulphur-containing drugs to male Wistar rats for five consecutive days led to a significant increase in hepatic cysteine dioxygenase activity. This increase in the production rate of cysteine sulphinic acid remained evident until returning to control levels four days after cessation of drug administration. These observations provide evidence that these two drugs interact with the intermediary biochemistry of sulphur compounds and may provide hitherto unappreciated insights into mechanisms by which therapeutic effects and adverse reactions may occur.

Administration, Oral↗
PubMed2004

The effect of cysteine analogues on the excretion of urinary sulphate in the rat following cysteine administration.

A major pathway for the production of sulphate within the mammalian body is known to be via the oxidative degradation of the sulphur moiety within the amino acid, L-cysteine. The ability of two structurally similar sulphur-containing drugs, the anti-rheumatic agent, D-penicillamine, and the mucoactive compound, S-carboxymethyl-L-cysteine, to interfere with this sulphate production was investigated. Co-administration to the male rat of D-penicillamine (p.o.) and S-carboxymethyl-L-cysteine (p.o.) with [35S]-L-cysteine (i.p.) led to a significant decrease in the subsequent urinary elimination of inorganic sulphate whilst having no measurable effect on organic sulphate excretion. The co-administration of L-valine, an amino acid not containing sulphur, had no effect. It is not known where, within the complex sequence of events surrounding the degradation of cysteine to sulphate, that D-penicillamine or S-carboxymethyl-L-cysteine may interact.

Animals↗
PubMed2003

Degradation to sulphate of S-methyl-L-cysteine sulphoxide and S-carboxymethyl-L-cysteine sulphoxide in man.

A nearly complete recovery of radioactivity was achieved over 14 days following the oral administration of [35S]-S-methyl-L-cysteine sulphoxide and [35S]-S-carboxymethyl-L-cysteine sulphoxide to four healthy male volunteers. The urine was the major pathway of excretion of radioactivity (c. 96% in 0-14 days; c. 59% in 0-24 hours), with the faecal route being relatively unimportant (c. 1.7% in 0-3 days). Inorganic sulphate was an important degradation product, incorporating a substantial proportion of radioactive sulphur derived from these molecules (c. 40% in 0-14 days; c. 20% in 0-24 hours). Subtle differences were noted in the pattern of radioactive sulphate excretion following administration of the two cysteine-sulphoxide compounds, suggesting that their sulphur-containing moieties may enter different catabolic routes.

Administration, Oral↗
PubMed2002

Fate of the anthelmintic, phenothiazine, in man.

1. Radiolabelled [(35)S]-phenothiazine has been administered orally to two healthy adult male volunteers (6 mg kg(-1) body weight). Faeces were the major route of excretion of radioactivity (68%), the remainder being eliminated via the urine (32%) with an estimated urinary half-life (biphasic) of 6-16 h. Over the 5 days of the study a complete recovery of radioactivity was achieved. 2. From urinary data, it was shown that metabolism occurred via ring carbon oxidation to form phenothiazone and thionol and via ring sulphur oxidation to form phenothiazine sulphoxide. The majority of urinary material (92%) was present in the form of conjugates of phenothiazine and phenothiazone. Only unchanged phenothiazine was detected in the faeces. Phenothiazine sulphoxide was reduced to phenothiazine during incubation with faecal homogenates.

Adult↗
PubMed2001

Characterization and purification of the vitamin K1 2,3 epoxide reductases system from rat liver.

The enzyme vitamin K1 2,3 epoxide reductase is responsible for converting vitamin K1 2,3 epoxide to vitamin K1 quinone thus completing the vitamin K cycle. The enzyme is also the target of inhibition by the oral anticoagulant, R,S-warfarin. Purification of this protein would enable the interaction of the inhibitor with its target to be elucidated. To date a single protein possessing vitamin K1 2,3 epoxide reductase activity and binding R,S-warfarin has yet to be purified to homogeneity, but recent studies have indicated that the enzyme is in fact at least two interacting proteins. We report on the attempted purification of the vitamin K1 2,3 epoxide reductase complex from rat liver microsomes by ion exchange and size exclusion chromatography techniques. The intact system consisted of a warfarin-binding factor, which possessed no vitamin K1 2,3 epoxide reductase activity and a catalytic protein. This catalytic protein was purified 327-fold and was insensitive to R,S-warfarin inhibition at concentrations up to 5 mM. The addition of the S-200 size exclusion chromatography fraction containing the inhibitor-binding factor resulted in the return of R,S-warfarin inhibition. Thus, to function normally, the rat liver endoplasmic reticulum vitamin K1 2,3 epoxide reductase system requires the association of two components, one with catalytic activity for the conversion of the epoxide to the quinone and the second, the inhibitor binding factor. This latter enzyme forms the thiol-disulphide redox centre that in the oxidized form binds R,S-warfarin.

Animals↗
PubMed2001

A review of xenobiotic metabolism enzymes in Parkinson's disease and motor neuron disease.

The role of xenobiotic metabolising enzymes (XMEs) in disease aetiology has been under investigation by numerous researchers around the world for the last two decades. The association of a number of defects in both phase I and phase II reactions with Parkinson's disease (PD) and motor neuron disease (MND) have been extensively studied. This review of the work of the group based initially at the University of Birmingham into the functional genomics of XMEs and neurodegenerative diseases has indicated that: 1. Sub-groups of patients with PD and MND can be identified with problems in xenobiotic metabolism by in vivo or in vitro methods. 2. 38-39% of the patients with MND/PD have a defect in the S-oxidation of the mucoactive drug, carbocysteine, by an unknown cytosolic oxidase(s). The odds risk ratio for the association of this defect with these diseases was calculated to be 10.21 for MND and 10.50 for PD. 3. Patients with PD appear to have an altered substrate specificity for monoamine oxidase B substrates in an in vitro platelet assay. 4. Patients with MND have an increased capacity to S-methylate aliphatic sulphydryl compounds in an in vivo challenge as well as an in vitro erythrocyte thiol methyltransferase assay. The results of over a decade of investigations into both PD and MND indicate that these are diseases with mutifactorial origins that encompass both genetic predisposition and environmental insult.

Adult↗
PubMed2000

Catalytic properties of CYP1A isoforms in the liver of an agnathan (Lampetra fluviatilis) and two species of teleost (Pleuronectes flesus, Anguilla anguilla).

The catalytic activity of CYP1A isoforms and the effect of mammalian CYP1A-specific inhibitors in liver S9 fractions were studied in an agnathan (River lamprey, Lampetra fluviatilis, 30-33 cm) and in two species of teleost fish (European flounder, Pleuronectes flesus, 11-18 cm and common eel, Anguilla anguilla, 31-48 cm). Ethoxyresorufin O-deethylation (EROD), caffeine N-demethylation/C-oxidation and phenacetin O-deethylation (POD) activity increased 3-4-fold in flounders and 17-46-fold in eels, 5 days after fish were injected (i.p.) with 100 mg kg(-1) benzo(a)pyrene (B[a]P). In lampreys, basal EROD activity was very low and no increase in activity was observed following exposure to B[a]P. While the apparent Michaelis constant (K(m)) for each assay showed only small changes after B[a]P injection, maximum reaction velocity (V(max)) values increased by up to 19- and 84-fold for EROD activity, 4- and 35-fold for caffeine-related metabolism and 4- and 19-fold for POD activity in flounders and eels, respectively. The mammalian CYP1A2 inhibitor furafylline (50 microM-1 mM) reduced activity in the EROD, caffeine and POD assays to 65, 21 and 20% of control values in flounders and to 85, 10 and 5% of control values in eels, respectively. By contrast, low concentrations (0.025-0.050 microM) of the mammalian CYP1A1 inhibitor ellipticine completely abolished EROD activity, but had no effect (up to 1 mM) on caffeine metabolism or POD activity in either species. While the inhibitor studies strongly suggest that two separate enzymes are present in flounders and eels, the monophasic Michaelis-Menten kinetics obtained in all the assays imply that only a single CYP1A protein is present that has substrate and inhibitor specificities characteristic of both mammalian CYP1A1 and CYP1A2 isoforms.

Anguilla↗
PubMed1999

Diurnal variation in the metabolism of S-carboxymethyl-L-cysteine in humans.

The routes of metabolism of S-carboxymethyl-L-cysteine in humans are dependent on the time of dosing. Administration of 750 mg of S-carboxymethyl-L-cysteine (Day 1) during the day at 8:00 AM followed by a 8:00 AM to 4:00 PM urine collection revealed that S-carboxymethyl-L-cysteine S-oxide was the major urinary metabolite produced. The 4:00 PM to midnight urine collection resulted in S-(carboxymethylthio)-L-cysteine being identified as the major urinary metabolite. However, the administration of 750 mg of S-carboxymethyl-L-cysteine (day 15) during the night at midnight and analysis of the midnight to 8:00 AM urine collection found that thiodiglycolic acid was the major urinary metabolite, whereas thiodiglycolic S-oxide was identified as the major urinary metabolite in the 8:00 AM to 4:00 PM urine collection. A diurnal variation in the metabolism of S-carboxymethyl-L-cysteine was seen and, in particular, the timing of S-carboxymethyl-L-cysteine administration had a profound effect on the identity of urinary S-oxide metabolites produced. After administration at 8:00 AM the urinary S-oxides produced were S-carboxymethyl-L-cysteine S-oxide and S-methyl-L-cysteine S-oxide but at midnight the major urinary S-oxide metabolite produced was thiodiglycolic acid S-oxide.

Adult↗
PubMed1998

Plasma levels of neuroexcitatory amino acids in patients with migraine or tension headache.

Plasma amino acids were analysed in patients with migraine with (9) and without (80) aura, in patients with tension headache (14) and in controls (62). The neuroexcitatory amino acids glutamic acid, glutamine, glycine, cysteic acid and homocysteic acid were elevated in migraine patients while total thiols (cysteine/cystine) were reduced. Patients with tension headache had values which were similar to those of controls. Tryptophan was elevated in migraine patients without aura only. Studies on two patients showed that the raised resting excitatory amino acid levels became still further elevated during a migraine attack. These results show that high concentrations of neurotransmitter amino acids occur normally in migraine patients and suggest that this profile may be a contributory factor in migraine attacks. Tension headache, however, has different biochemical parameters.

Adult↗
PubMed1997

Platelet sulphotransferase activity, plasma sulphate levels and sulphation capacity in patients with migraine and tension headache.

Activity of both the M- and P-forms of sulphotransferase (ST) was measured in platelets from patients with migraine, tension headache and controls. Mean PST values were 0.065 +/- 0.023 and 0.057 +/- 0.052 nmol/mg protein/min for migraine patients with and without aura. The corresponding values for tension headache and controls were 0.122 +/- 0.059 and 0.127 +/- 0.093 nmol/mg protein/min respectively (p < 0.05). Mean MST values were not different for any of the groups, and MST and PST activities measured in two patients during a migraine attack were not significantly altered from baseline levels. Mean plasma inorganic sulphate concentrations and paracetamol metabolites were not significantly different in any of the groups studied. The results suggest that PST activity may be a factor in the aetiology of migraine.

Acetaminophen↗
PubMed1996

Human metabolism of paracetamol (acetaminophen) at different dose levels.

Urine (0-24 h) was collected from five subjects on separate occasions following the ingestion of paracetamol at five different dose levels (500, 750, 1000, 1250, 1500 mg) which spanned the normal therapeutic range. The major urinary metabolites were sulphuric and glucuronic acid conjugates which together accounted for around 50% of the administered dose. Unchanged paracetamol excretion was low (5-20%). This situation was similar over the entire dose range. These findings are discussed in relation to previous single dose studies reported in the literature.

Acetaminophen↗
PubMed1995

Thalidomide-induced neuropathy and genetic differences in drug metabolism.

A pharmacogenetic predisposition to thalidomide-induced neuropathy has been investigated. Differences of drug metabolism were examined in 16 patients with severe orogenital ulceration, who were treated with thalidomide (< or = 200 mg/day) for 0.3-5.0 years. Eight had evidence of early peripheral neuropathy according to nerve conduction studies. Rates of C-hydroxylation, N-acetylation, and conjugation reactions with sulphate, glucuronide and glycine, were tested with the probe compounds debrisoquine, sulphadimidine, paracetamol and aspirin, respectively. Urinary drug metabolites were analysed by high pressure liquid chromatography. Results were compared with 16 healthy age- and sex-matched volunteers. Of the patients 6.25% and 13.3% of the controls had a poor Debrisoquine Hydroxylator Ratio (DMR); none of the patients with neuropathy had a poor DMR as compared to 12.5% without neuropathy. Of the patients 40.0% and 35.7% of the controls were slow acetylators; 28.6% with neuropathy were slow acetylators as opposed to 50% without neuropathy. Similarly, there were no significant differences in rates of conjugation between groups. All unaffected patients were active smokers, whereas only two of those with neuropathy smoked. Cumulative dose or duration of therapy were unrelated to risk of neuropathy. In conclusion, changes of nerve conductivity are a frequent and unpredictable adverse effect of thalidomide (< or = 200 mg/day), although smoking may have a protective action against their development. Nerve conduction studies are required before and during treatment, irrespective of the prescribed dose.

Acetylation↗
PubMed1994

Pathways of cysteine metabolism in MND/ALS.

Analysis of plasma from MND/ALS patients has shown no significant differences in metabolism of cysteine derivatives, although a sub-set of the population has raised glutamate values. Cysteine dioxygenase was found to have reduced activity in vitro, consistent with previous findings of a high plasma cysteine/sulphate ratio.

Adult↗
PubMed1994

D-penicillamine metabolism in neurodegenerative diseases: an in vivo/in vitro sulphydryl methylation study.

1. D-Penicillamine (125 mg) was administered orally to control (healthy volunteers), Parkinson's and Motor Neurone Disease patients following an overnight fast. 2. Blood was collected at 08:00 h for the preparation of red blood cell membranes used in the in vitro S-methylation studies. Urine was collected from 08:00 to 16:00 h and analysed for D-penicillamine and its metabolites. 3. Metabolism occurred via S-methylation, N-acetylation and disulphide formation. Both the Parkinson's and Motor Neurone Disease patients excreted significantly higher median levels of S-methyl-D-penicillamine in the urine than the controls (177 and 209% more for the Parkinson's and Motor Neurone Disease patients respectively). 4. The in vitro and in vivo production of S-methyl-D-pencillamine was highly correlated in the control (rs = 0.936), Parkinson's (0.986) and Motor Neurone Disease (0.752) populations.

Adult↗