S. Sturman

S-METHYLATION IN MOTORNEURON DISEASE AND PARKINSON'S DISEASE

Thiolmethyltransferase activity has been measured in newly diagnosed, untreated patients with idiopathic Parkinsons 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]).

Xenobiotic metabolism in Alzheimer's disease

Using 5 methods, we assessed the ability of patients with a clinical diagnosis of Alzheimers 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.

Metabolism of low-dose paracetamol in patients with chronic neurological disease

1. Low dose (500 mg) paracetamol (acetaminophen) was administered to patients with Parkinsons 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; Parkinsons 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 Parkinsons disease and motor neurone disease respectively. These differences are statistically significant (p less than 0.001).

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 Parkinsons 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.

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), Parkinsons 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 Parkinsons 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 Parkinsons 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), Parkinsons (0.986) and Motor Neurone Disease (0.752) populations.

Xenobiotic enzyme profiles and Parkinson's disease

Xenobiotic enzymic systems have been studied in Parkinsons disease. Platelet monoamine oxidage-B activity is increased by the use of phenylethylamine but decreased by the use of dopamine as substrate. Enzymes involved with sulfur oxidation and methylation are underactive.

Hereditary variation of liver enzymes involved with detoxification and neurodegenerative disease

SummaryEnzymes involved with the metabolic transformation of xenobiotics have recently been studied in patients with the neurodegenerative diseases, Alzheimers disease, Parkinsons disease and motor neurone disease. Defects were detected in sulphur pathways and also, in the case of Parkinsons disease, in monoamine oxidase B. The possibility exists that the ability to cope safely with endogenous and exogenous substances which have neurotoxic properties is important in the pathogenesis of these diseases. Potentially such individuals could be identified preclinically and these diseases postponed by reduction in the load of toxin or modification of the relevant enzymic activity.