MAO-B and Parkinson's disease.
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Biomedical subjects
R H Waring
Publications and source records attributed to R H Waring.
Pesticide toxicity and motor neuron disease.
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Humans↗
Xenobiotic metabolism in Alzheimer's disease.
Using 5 methods, we assessed the ability of patients with a clinical diagnosis of Alzheimer's disease (AD) to handle xenobiotics. Patients with AD, compared with controls, have reduced sulfoxidation of the probe drug S-carboxymethyl-L-cysteine; they also form less of the sulfate conjugate of acetaminophen. In addition, they have lower activity of the enzyme thiolmethyltransferase. In contrast, the capacity to oxidize debrisoquin and to acetylate sulfamethazine was normal. These findings suggest that a major risk factor for the development of AD is a skewed capacity for xenobiotic metabolism especially of compounds containing sulfur.
Acetaminophen↗
Metabolism of low-dose paracetamol in patients with chronic neurological disease.
1. Low dose (500 mg) paracetamol (acetaminophen) was administered to patients with Parkinson's disease, motor neurone disease and to age-matched controls. 2. At this low dose level the controls excreted proportionately more sulphate and less glucuronide conjugate than has been reported for administration of 1000 mg of paracetamol. 3. Both groups of patients with chronic neurological disease excreted decreased amounts of paracetamol sulphate (control mean 11.2 +/- 5.4% dose; Parkinson's disease 3.9 +/- 3.7%; motor neurone disease, 5.0 +/ 4.1%). 4. The mean ratio of excretion of paracetamol sulphate/paracetamol glucuronide was 5.6 +/- 11.7 in controls, but 1.1 +/- 1.7 and 1.2 +/- 1.7 in Parkinson's disease and motor neurone disease respectively. These differences are statistically significant (p less than 0.001).
Acetaminophen↗
S-methylation in motorneuron disease and Parkinson's disease.
Thiolmethyltransferase activity has been measured in newly diagnosed, untreated patients with idiopathic Parkinson's disease and motorneuron disease, and in normal volunteers. In Parkinsonian patients, mean thiolmethyltransferase activity was low (300 U/mg protein [SD 96]) compared with that in controls (947 [409]), whereas activity was high in patients with motorneuron disease (2077 [825]).
Adult↗
Platelet monoamine oxidase-B activity in Parkinson's disease.
Platelet MAO-B levels have been investigated in seventeen consecutively diagnosed and previously untreated patients with idiopathic Parkinson's disease using the non-hydroxylated catecholamine, beta-phenylethylamine, as substrate. Patients with Parkinson's disease had MAO-B activity levels that were considerably higher than sex and age matched normal controls or patients with Motor neurone disease or Myasthenia gravis.
Adult↗
The deficiency of sulfoxidation of S-carboxymethyl-L-cysteine.
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Biotransformation↗
Xenobiotic metabolism in Parkinson's disease.
We studied 68 patients with Parkinson's disease (PD) with probe drugs to determine whether a defect in metabolism might be an etiologic factor and found no difference between patients and controls in their ability to form the 4-hydroxy metabolite of debrisoquin. However, using S-carboxymethyl-L-cysteine, 63.2% (43/68) of PD patients had reduced S-oxidation capacity, while 35.3% (24/68) produced no sulfoxides (controls, 35.2% and 2.5%). When we studied acetaminophen (paracetamol) metabolism, only 29.6% of PD patients excreted greater than 5% of the dose as the sulfate conjugate; the corresponding figure for controls was 83.9%. These results suggest a deficiency in detoxication pathways involving sulfur metabolism. PD patients may be unusually susceptible to exogenous or even endogenous toxins.
Acetaminophen↗
The fate of cimetidine sulphoxide in the guinea pig.
1. An oral dose of cimetidine given to guinea pigs was totally excreted in 3 days, divided equally between urine and faeces. 2. Only 40% of an oral dose of cimetidine sulphoxide was voided in 3 days, the remainder being found in the mesentery and omental tissues. 3. In contrast, 90% of an i.v. dose of cimetidine sulphoxide was excreted in urine in 24 h. 4. Approx. 20% of an oral dose of both cimetidine (17.2%) and cimetidine sulphoxide (24.9%) was secreted in bile during the first day. 5. The major metabolic routes encountered were sulphoxidation and sulphoxide reduction.
Administration, Oral↗
Xenobiotic metabolism in motor neuron disease.
Debrisoquine, carbocysteine, and paracetamol were selected as safe drugs to investigate the ability of the liver's microsomal system to oxidise carbon, oxidise sulphur, and conjugate sulphate in patients with motor neuron disease (MND), other hospital patients, and healthy volunteers. Subjects with poor sulphur-oxidising and sulphur-conjugating activities were heavily over-represented in the MND group.
Acetaminophen↗
Poor sulphoxidation ability in patients with food sensitivity.
Patients with well defined reactions to foods were examined for their ability to carry out both sulphur and carbon oxidation reactions by using carbocisteine and debrisoquine as probe compounds. The proportion of poor sulphoxidisers (58 of 74) was significantly greater than that of a previously determined normal control population (67 of 200; p less than 0.005). The proportion of poor carbon oxidisers was not significantly different from the controls. Metabolic defects may play a part in the pathogenesis of adverse reactions to foods.
Adult↗
High incidence of poor sulfoxidation in patients with primary biliary cirrhosis.
An impaired sulfoxidation pathway has been implicated in the pathogenesis of chlorpromazine-induced hepatotoxicity. Since some patients with chronic chlorpromazine-induced cholestasis may have features of primary biliary cirrhosis, we studied the ability to sulfoxidate the amino acid analogue S-carboxymethyl-cysteine in 44 patients with primary biliary cirrhosis and in two control groups--one without liver disease and one with a variety of liver diseases other than primary biliary cirrhosis. Poor sulfoxidation was observed in 84 percent of the patients with primary biliary cirrhosis, as compared with 24 percent of patients with other liver diseases and 22 percent of normal controls (P less than 0.0005 for both comparisons). Poor sulfoxidation did not correlate with the degree of hyperbilirubinemia or histologic severity of liver disease in any of the groups studied. There was an inverse correlation with age only in the patients with primary biliary cirrhosis (r = -0.44, P less than 0.001). Liver transplantation was performed in six of the patients and improved sulfoxidation in five; in the four with primary biliary cirrhosis, sulfoxidation improved from poor to good or intermediate. We conclude that poor sulfoxidation is closely associated with primary biliary cirrhosis but not with the other liver diseases we studied.
Adolescent↗
A proposed mechanism for chlorpromazine jaundice--defective hepatic sulphoxidation combined with rapid hydroxylation.
On the basis of previous experimental studies we postulated that individuals who were phenotypically good hydroxylators but poor sulphoxidisers would be susceptible to chlorpromazine jaundice. Sulphoxidation capacity was assessed in 12 subjects with a history of chlorpromazine jaundice, using S-carboxymethyl-L-cysteine as an in vivo probe. Following an oral dose of 750 mg, unchanged compound and sulphoxide metabolites were measured in urine. All 12 subjects (100%) were shown to be poor sulphoxidisers compared to 22% of normal controls (P less than 0.001) and 23.8% of liver disease controls (P less than 0.001). No subjects with a history of chlorpromazine jaundice had an impaired hydroxylation capacity as assessed by recovery of 4-hydroxydebrisoquine in urine following oral debrisoquine. The results support the hypothesis and demonstrate an inherent metabolic basis of susceptibility to chlorpromazine jaundice.
Adult↗
Pharmacogenetics of the S-oxidation of S-carboxymethyl-L-cysteine.
The pharmacogenetics of S-carboxymethyl-L-cysteine (SCMC) have been studied in detail. When results from administration of SCMC to 200 volunteers were analysed, there was seen to be a wide interindividual variation in the percentage of sulphoxide metabolites excreted. Computer assisted analysis suggested that the population distribution observed could be most economically represented as two overlapping Gaussian distributions with the smaller mode representing poor sulphoxidisers. This phenomenon appears to be largely genetic in origin and to behave as though controlled by one autosomal recessive gene, but environmental factors may also be important. Poor sulphoxidisers seem to be overrepresented in certain patient populations with chronic diseases. These findings are discussed in terms of oxidative metabolism of sulphur-containing compounds.
Animals↗
The metabolism of 35S-D-penicillamine in man.
1. The excretion and metabolism of 35S-D-penicillamine (200 mg orally) was studied in four healthy male volunteers. 2. The major route of excretion was the urine with 82% of the administered dose being voided over three days (73% during the first 24 h); the remainder was excreted in the faeces. 3. Metabolism occurred via the pathways of S-methylation, N-acetylation and disulphide formation. Extensive degradation of the molecule was observed with the production of large amounts of inorganic sulphate.
Administration, Oral↗
D-penicillamine metabolism: in vitro studies of S-oxidation mechanisms.
The metabolism of D-penicillamine was studied in vitro using microsomal and cytosolic fractions of liver from DA-strain rats. Formation of inorganic sulphate, presumably via an S-oxidative pathway, was catalysed by both fractions. However, microsomal S-oxidation was higher in female animals than males, the sex differences being reversed with cytosolic fractions. The total yield of inorganic sulphate was similar for both sexes. Cytochrome P-450 isoenzymes did not appear to be directly involved.
Animals↗
Odorous urine following asparagus ingestion in man.
The production of odorous urine after the ingestion of asparagus has been shown to occur in 43% of 800 volunteers investigated. This characteristic is reproducible over a 12-month-period and has been shown to remain with individuals for virtually a lifetime. Family studies suggest that the ability to produce the odorous urine is inherited as an autosomal dominant trait.
Female↗
Sodium aurothiomalate toxicity and sulphoxidation capacity in rheumatoid arthritic patients.
The association between sulphoxidation capacity and sodium aurothiomalate toxicity was investigated in 65 patients undergoing treatment for rheumatoid arthritis. Of those showing side-effects, 30/37 (81%) were also poor sulphoxidizers compared with only 9/28 (32%) in the group not displaying adverse reactions. A patient with poor sulphoxidation had a nine-fold greater risk of developing toxicity. The prior measurement of sulphoxidation capacity may help to identify those patients most susceptible to the deleterious effects of this drug.
Adult↗