Adrian C. Williams

Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease

The pathogenesis of Parkinsons disease may be influenced by genetic and environmental factors. Cytochrome P450 mono-oxygenases help to protect against toxic environmental compounds and individual variations in cytochrome P450 expression might, therefore, influence susceptibility to environmentally linked diseases. The frequency of mutant CYP2D6 alleles was studied in 229 patients with Parkinsons disease and 720 controls. Individuals with a metabolic defect in the cytochrome P450 CYP2D6-debrisoquine hydroxylase gene with the poor metaboliser phenotype had a 2.54-fold (95% Cl 1.51-4.28) increased risk of Parkinsons disease. Determination of CYP2D6 phenotype and genotype may help to identify those at greatest risk of Parkinsons disease and may also help to identify the environmental or metabolic agents involved in the pathogenesis of this disease.

Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson's and Alzheimer's disease

Elevated plasma cysteine to sulphate ratios were found in patients with Motor neurone disease (MND), Parkinsons disease (PD) and Alzheimers disease (AD). Cysteine and sulphate were measured by colourimetric methods. Following recent discovery of a defect in sulphoxidation and sulphation of xenobiotics in these diseases, this finding confirms that endogenous sulphur metabolism is disturbed. The mean cysteine:sulphate ratios (x 10(3] in fasting early morning plasma were 506, 521 and 477 for MND, PD and AD whereas it was 96 for normal controls (P less than 0.001). This excess of cysteine thiol groups may interfere with neural protein function. The deficiency of sulphate ions may lead to reduced xenobiotic detoxification.

Raised cerebrospinal-fluid copper concentration in Parkinson's disease.

The cerebrospinal-fluid copper concentration, measured by electrothermal atomisation/atomic absorption spectrophotometry, was significantly higher in 24 patients with untreated, idiopathic Parkinsons disease than in a control population of 34 patients (p less than 0.001). The difference in the in-vitro capacity of copper to damage DNA, measured by the phenanthroline assay was even greater. The high phenanthroline-copper concentration correlated with disease severity (p = 0.02) and with the rate of progression of disease (p less than 0.05). A possible role is suggested for copper-catalysed oxidative mechanisms in the pathogenesis of Parkinsons disease.

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.

High expression of nicotinamide N-methyltransferase in patients with idiopathic Parkinson's disease

We have previously speculated that elevated levels of nicotinamide N-methyltransferase (NNMT), the primary catabolic enzyme of nicotinamide, may result in reduced Complex I activity in idiopathic Parkinsons disease (IPD) in two ways: (1) reduction in the levels of nicotinamide available for nicotinamide adenine dinucleotide synthesis; and (2) increased methylation of compounds such as tetrahydroisoquinolines and beta-carbolines, which are potent Complex I inhibitors. Expression of NNMT was assessed in 91 cerebella (53 IPD, 38 control) using immunohistochemistry coupled with quantitative digital image analysis. Control cerebella showed a distribution of expression ascribed to low, intermediate and high expressors with ratios of 1:2:1 categories. Expression in the parkinsonian cerebella was significantly higher than in the control group (control group median expression 17%, mean expression 16.6%, range 0-51%, standard deviation 11.4%, standard error 1.9%; IPD group median expression 46%, mean expression 53.7%, range 21-100%, standard deviation 23.4%, standard error 3.2%; P<0.0001; unpaired t-test with Welch correction (parametric) and Mann-Whitney U-test (non-parametric)). These results confirm that NNMT expression is elevated in IPD, which may ultimately lead to neurodegeneration via a reduction in Complex I activity.

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]).

Cytochrome P450 1B1 mRNA in the human central nervous system.

AIMS: To study the expression of CYP1B1 in a variety of human and rat cell lines as a means of identifying a new tool for the investigation of gene regulation. In addition, to identify the expression of cytochrome P450 1B1 (CYP1B1) in different regions of the central nervous system (CNS). METHODS: Reverse transcription-polymerase chain reaction followed by cloning and sequencing were used to detect the expression of CYP1B1 in human cell lines. Poly A+ mRNA from the human spinal cord and from different brain regions was analysed using a CYP1B1 probe labelled with 32PdCTP. RESULTS: Expression of CYP1B1 was shown in a human astrocytoma cell line (MOG-G-CCM). CYP1B1 mRNA was expressed in a variety of regions of the CNS but with a distinct regional specificity. Expression was highest in the putamen. CONCLUSIONS: The expression of CYP1B1 in a human astrocytoma enables this cell line to be used in further studies of regulation and function of this gene. The demonstration that CYP1B1 mRNA is expressed in a variety of regions of the CNS suggests a role for this gene in brain and spinal cord metabolism. The regional specificity of expression might explain the focal damage of certain human neurodegenerative diseases.

Evaluating drug treatments for Parkinson's disease: how good are the trials?

Keith Wheatley and colleagues make the case that most trials of drug treatment for Parkinsons disease have crucial methodological faults—and provide little reliable evidence on differences between classes of drugs Parkinsons disease is one of the commonest causes of disability in older people, with over 100 000 patients in the United Kingdom and at least 8000 new cases diagnosed annually. Prevalence and incidence will both increase with the ageing population and the reduction in competing causes of mortality such as stroke and coronary heart disease.1 No cure currently exists, and medical treatment is directed towards alleviating symptoms.2 Levodopa relieves symptoms in most patients with Parkinsons disease, but long term use of levodopa is associated with motor complications such as involuntary movements (dyskinesias), along with a shortened response to each dose (wearing-off phenomenon) and unpredictable “on-off” fluctuations. A number of other drugs have been used,3 either alone or with reduced doses of levodopa, in an attempt to delay the onset of motor complications in early Parkinsons disease or to control complications once they have developed. These agents have primarily been from three classes of drug: dopamine agonists, monoamine oxidase type B inhibitors, and catechol- O -methyltransferase inhibitors. Many randomised controlled trials have evaluated these drugs, but uncertainty about their relative effectiveness remains. This review assesses the methods used in these trials to reveal the quality of the existing evidence base. #### Summary points The prevalence of Parkinsons disease will increase as the population ages, making it important to identify reliably the most effective drug therapy Although many randomised controlled trials have evaluated the efficacy of different classes of drugs in both early and later Parkinsons disease, uncertainty about best treatment remains because of small numbers, inadequate follow up, and inappropriate end points Much larger trials are needed with long term follow …

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).

XENOBIOTIC METABOLISM IN MOTORNEURON DISEASE

Debrisoquine, carbocysteine, and paracetamol were selected as safe drugs to investigate the ability of the livers 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.