L-dopa upregulates the expression and activities of methionine adenosyl transferase and catechol-O-methyltransferase.
High nonphysiological doses of l-dopa are administered to Parkinson's disease (PD) patients, to replenish the depleted dopamine (DA). A large portion of the administered L-dopa and the newly formed DA undergoes methylation by reacting with S-adenosyl-L-methionine (SAM). In the process SAM, as well as L-dopa and DA, is utilized and great demands are placed on the transmethylation system. In this study we investigated whether L-dopa increases the transmethylation process by inducing methionine adenosyl transferase (MAT), the enzyme that produces SAM, and catechol-O-methyl transferase (COMT), the enzyme that transfers the methyl group from SAM to L-dopa and DA. Swiss Webster mice were injected with L-dopa, four times/day, for 1 to 16 days. Brain DA, 3-O-methyldopa (3-OMD), SAM, S-adenosylhomocysteine (SAH), MAT, and COMT were measured following a 24-h withdrawal period. An increase of 264% of brain DA occurred at days 2 and 3 after which it tapered to about 164% of control. The brain level of 3-OMD increased to 870% of the control. SAM was increased by 44% after the sixth day and SAH level was about double after the second day. After day 3, MAT activity was increased by about 35%. Western blot analysis showed that MAT is more clearly characterized in 10% mercaptoethanol reducing buffer in which 31.5-, 38- (beta), and 48-kDa (alpha1/alpha2) subunits were distinctly revealed. The induction of the 38-kDa and, more prominently, the 48-kDa subunits of MAT and the potential transactivator proteins of MAT, c-Jun/AP-1, was evident by day 6. The 31.5-kDa subunit was downregulated. COMT was detected as 24.7-, 30-, and 47.5-kDa bands in the brain, consistent with the membrane-bound COMT I (MB-COMT) and the dimeric COMT II. The 24.7- and the 30-kDa MB-COMT bands were induced in the brain by day 6 and peaked on day 9. The highlight of the study is the fact that L-dopa induces the enzymes MAT and COMT. In addition, the downturn in brain DA after the sixth day coincides with the increase in SAM and the 48-kDa MAT protein. Thus, during PD treatment with L-dopa the induction of MAT and COMT is likely to occur and in turn increase the methylation and reduction of L-dopa and DA that may help cause the tolerance or the wearing-off effect developed to L-dopa.
Zhao
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WQ
College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, Florida 32307, USA.
Latinwo
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L
Liu
X X
XX
Lee
E S
ES
Lamango
N
N
Charlton
C G
CG
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D007668:Kidney / Q000201:enzymology; D007980:Levodopa / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D008716:Methionine Adenosyltransferase / Q000378:metabolism*; D051379:Mice; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D014443:Tyrosine; D007980:Levodopa; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D002394:Catechol O-Methyltransferase; D008716:Methionine Adenosyltransferase; C008404:3-methoxytyrosine; D004298:Dopamine