Parkinson's disease and CYP1A2 activity

• Published in: British journal of clinical pharmacology 2000-10, Vol.50 (4), p.303-309
• Main Authors: Forsyth, J. T., Grünewald, R. A., Rostami‐Hodjegan, A., Lennard, M. S., Sagar, H. J., Tucker, G. T.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Caffeine - metabolism; CYP2E1; Cytochrome P-450 CYP1A2 - metabolism; Drug Disposition; Female; Humans; Male; Middle Aged; Parkinson Disease - enzymology; Parkinson Disease - metabolism; Parkinson's disease; Reproducibility of Results; Saliva - metabolism; Theophylline - metabolism
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1046/j.1365-2125.2000.00259.x

Aims MPTP, a neurotoxin which induces parkinsonism is partially metabolized by the enzyme CYP1A2. Smoking appears to protect against Parkinson's disease (PD) and cigarette smoke induces CYP1A2 activity. Thus, we investigated the hypothesis that idiopathic PD is associated with lower CYP1A2 activity using caffeine as a probe compound. Methods CYP1A2 activity was assessed using saliva paraxanthine (PX) to caffeine (CA) ratios. Caffeine half‐life was also estimated from salivary concentrations of caffeine at 2 and 5 h post dose. 117 treated and 40 untreated patients with PD and 105 healthy control subjects were studied. Results PX/CA ratios were 0.57, 0.93 and 0.77 in treated patients, untreated patients and healthy control subjects, respectively, with no significant differences between study groups (95% CI: treated patients vs controls −0.24, 0.57; untreated patients vs controls −0.75, 0.35). However, patients with PD (treated or untreated) had caffeine half‐lives shorter than that in controls (treated patients: 262 min, untreated patients: 244 min, controls: 345 min; 95% CI: controls vs treated patients 23, 143 (P = 0.003); controls vs untreated patients 19, 184 (P = 0.011)). Amongst the patients with PD, caffeine half‐life was also inversely related to the age of onset of disease (P = 0.012); gender and concomitant drugs did not influence this significantly. Conclusions Based on PX/CA ratio, there was no evidence of decreased CYP1A2 activity in patients compared with control subjects. The observed decrease in the elimination half‐life of caffeine in PD may be caused by increased CYP2E1 activity, an enzyme that also contributes to the metabolism of caffeine. The latter warrants further investigation.