Effects of L-dopa treatment on methylation in mouse brain: implications for the side effects of L-dopa.
The effects of L-dopa on methylation process in the mouse brain were investigated. The study is based on recent findings that methylation may play an important role in Parkinson's disease (PD) and in the actions of L-dopa. The methyl donor, S-adenosylmethionine (SAM) and a product of SAM, methyl beta-carboline, were shown to cause PD-like symptoms, when injected into the brain of animals. Furthermore, large amounts of 3-O-methyl dopa, the methyl product of L-dopa, are produced in PD patients receiving L-dopa treatment, and L-dopa induces methionine adenosyl transferase, the enzyme that produces SAM. The results show that, at 0.5 hr, L-dopa (100 mg/kg) decreased the methyl donor, S-adenosylmethionine (SAM) by 36%, increased its metabolite S-adenosylhomocysteine (SAH) by 89% and increased methylation (SAH/SAM) by about 200%. All parameters returned to control values within 4 hr. But 2, 3 and 4 consecutive injections of L-dopa, given at 45 min intervals, depleted SAM by 60, 64 and 76% and increased SAM/SAH to 818, 896, and 1524%. L-dopa (50, 100 and 200 mg/kg) dose-dependently depleted SAM from 24.9 +/- 1.7 nmol/g to 13.0 +/- 0.8, 14.7 +/- 0.8 and 7.7 +/- 0.7 nmol/g, and increased SAH from 1.88 +/- 0.14 to 3.43 +/- 0.26, 4.22 +/- 0.32 and 6.21 +/- 0.40 nmol/g. Brain L-dopa was increased to 326, 335 and 779%, dopamine to 138, 116 and 217% and SAH/SAM to 354, 392 and 1101%. The data show that L-dopa depletes SAM, and increases methylation 4-5 times more than dopamine, therefore, methylation may play a role in the actions of L-dopa. This and other studies suggest that the high level of utilization of methyl group by L-dopa leads to the induction of enzymes to replenish SAM and to increase the methylation of L-dopa as well as DA. These changes may be involved in the side effects of L-dopa.
Liu
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College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee 32307, USA.
Wilson
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Charlton
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D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects*; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007980:Levodopa / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008716:Methionine Adenosyltransferase / Q000378:metabolism; D008745:Methylation / Q000187:drug effects*; D051379:Mice; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet
D000978:Antiparkinson Agents; D007980:Levodopa; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D002394:Catechol O-Methyltransferase; D008716:Methionine Adenosyltransferase; D004298:Dopamine