[Sparteine oxidation by hepatic cytochrome P-450 in patients with Parkinson's disease]

Abstract

MPTP-induced parkinsonism has revived interest in the role of environmental factors in the etiology of Parkinson's disease. Many potentially neurotoxic substances are detoxified by hepatic cytochrome P-450 through oxidation. Barbeau et al. (1985) reported that significantly more parkinsonian patients than control subjects had defective 4-hydroxylation of debrisoquine. A close correlation between polymorphic oxidation of debrisoquine and sparteine had been observed in Caucasians, suggesting that the oxidative metabolism of these two drugs is under a common genetic control. We report here sparteine oxidation in 71 parkinsonian patients, including 26 young-onset subjects. Each subject was given 100 mg of sparteine sulfate orally, and urine was collected for 6 hours. Sparteine and its dehydrometabolites were analyzed in urine using the method of gas chromatography. Metabolic ratio (MR) was calculated from: (amount of sparteine)/(amount of 2-, plus 5-dehydrosparteine). Subjects with an MR greater than 20 were defined as poor metabolizers (PMs). No PM was observed in our parkinsonian subjects, but the distribution of MR in parkinsonian subjects was significantly deviated to the higher MR value (mean +/- SD: 1.19 +/- 1.27, range: 0.02-6.12) than healthy controls (0.60 +/- 0.61, 0.11-3.07). This is probably due to a higher frequency of intermediate metabolizers in parkinsonian patients having partial defect of sparteine oxidation. Mild negative correlation (rs = -0.45) was noted between the MR and the age of onset in parkinsonian subjects. When the 71 patients were divided into two groups according to the age of onset, a larger difference in the MR value was found when subjects were divided at the age of 45 years (p < 0.005) compared with subdivision at the age of 40 years (p < 0.02). Our results suggest that slower metabolism by hepatic debrisoquine-sparteine type cyt. P-450 is one of the contributory factors for the development of Parkinson's disease.