Evidence for L-dopa incorporation into cell proteins in patients treated with levodopa.
Levodopa (L-dopa) is the most widely used agent for the symptomatic relief of Parkinson's disease. There is concern that chronic L-dopa treatment may be detrimental, with some studies suggesting that L-dopa may be neurotoxic. A potentially important mechanism whereby L-dopa may exert neurotoxic effects has been overlooked: that of the incorporation of L-dopa into proteins by protein synthesis. L-Dopa competes with tyrosine as a substrate in protein synthesis in vitro. We provide evidence that L-dopa can also be incorporated into proteins in vivo. Blood from L-dopa-treated and -non-treated patients was separated into protein, erythrocyte and lymphocyte fractions and levels of protein-incorporated dopa quantified by HPLC. Levels of protein-incorporated dopa were significantly increased in lymphocyte cell proteins from L-dopa-treated patients. This has not arisen from oxidative pathways as there was no evidence of oxidative damage to proteins. In addition, there was no increase in protein-incorporated dopa in erythrocytes, which are not actively synthesizing proteins. We suggest that protein-incorporated dopa could also be generated in the CNS. The accumulation of protein-incorporated dopa in cells is associated with oxidative stress and impaired function and could contribute to some of the problems associated with long-term L-dopa treatment.
Rodgers
Kenneth J
KJ
The Cell Biology Group, The Heart Research Institute, Camperdown, Sydney, New South Wales, Australia. rodgersk@hri.org.au
Hume
Peter M
PM
Morris
John G L
JG
Dean
Roger T
RT
D000368:Aged; D000978:Antiparkinson Agents / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006801:Humans; D006868:Hydrolysis; D007980:Levodopa / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008750:Methyldopa / Q000097:blood / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism
D000978:Antiparkinson Agents; D011506:Proteins; D007980:Levodopa; D008750:Methyldopa