Inhibition of dopamine biosynthesis by tetrahydropapaveroline.
Tetrahydropapaveroline (THP) at 5-15 microM has been found to induce L-DOPA-induced oxidative apoptosis in PC12 cells. In this study, the inhibitory effects of THP on dopamine biosynthesis in PC12 cells and tyrosine hydroxylase (TH) activity in bovine adrenal were investigated. Treatment of PC12 cells with THP at 2.5-10 microM significantly decreased the intracellular dopamine content in a concentration-dependent manner (21.3% inhibition at THP 10 microM). The activity of TH was also inhibited by the treatment with THP at 2.5-10 microM (23.4% inhibition at 10 microM). In addition, THP had an inhibitory effect on bovine adrenal TH (IC50 value, 153.9 microM). THP exhibited uncompetitive inhibition on bovine adrenal TH with a substrate l-tyrosine with the Ki value with L-tyrosine of 0.30 mM. Treatment with L-DOPA at 20-50 microM increased the intracellular dopamine content in PC12 cells and the increase in dopamine content by L-DOPA was in part inhibited when L-DOPA (20 and 50 microM) was associated with THP at non-cytotoxic (5-10 microM) or cytotoxic (15 microM) concentration ranges. However, the reduction of dopamine content by THP (15 microM) or THP (15 microM) associated with L-DOPA (20 and 50 microM) in PC12 cells was inversed by the antioxidant N-acetyl-cysteine (0.1mM). These results indicate that THP at 5-10 microM decreases the basal dopamine content and reduces the increased dopamine content induced by L-DOPA in part by the inhibition of TH activity, and that THP at 15 microM does by oxidative stress in PC12 cells.
Kim
Yu Mi
YM
College of Pharmacy, and Research Center for Bioresource and Health, Chungbuk National University, 12, Kaeshin-Dong, Cheongju 361-763, South Korea.
Kim
Mi Na
MN
Lee
Jae Joon
JJ
Lee
Myung Koo
MK
D000313:Adrenal Medulla / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002417:Cattle; D004298:Dopamine / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000633:toxicity; D007980:Levodopa / Q000494:pharmacology; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D013765:Tetrahydropapaveroline / Q000378:metabolism* / Q000633:toxicity; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000975:Antioxidants; D004791:Enzyme Inhibitors; D007980:Levodopa; D013765:Tetrahydropapaveroline; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine