Dialkyldithiocarbamates inhibit tyrosine hydroxylase activity in PC12 cells and in fibroblasts that express tyrosine hydroxylase.
Dithiocarbamates and CS2 have been associated with neurobehavioural changes suggestive of central dopaminergic dysfunction. Diethyldithiocarbamate (DEDC), dimethyldithiocarbamate (DMDC), and methyldithiocarbamate (MDC) were examined for their ability to inhibit tyrosine hydroxylase (TH) activity in PC12 cells and transfected CHO fibroblasts that expressed TH (CHO/TH) activity when tetrahydrobiopterin (BH4) was added to medium. DEDC or DMDC did not significantly alter viability of PC12 cells or CHO/TH cells at < or = 100 microM for 18 h; the EC50 for each compound was approximately 5 mM in both cell lines. In contrast, the EC50 for MDC was 41 or 74 microM in PC12 or CHO/TH cultures, respectively. There was no change in immunodetectable levels of TH in PC12 or CHO/TH cells following exposure to subcytotoxic concentrations of dithiocarbamates. DEDC and DMDC (5 to 100 microM) produced concentration-dependent reductions in PC12 cell dopamine and dopac levels as well as in dopa levels in CHO/TH cultures. Reduction of PC12 catechols was not due to altered vesicular storage. In vitro PC12 TH activity was 80.2 +/- 3.4% or 82.4 +/- 2.9% of control following exposure to 100 microM DEDC or DMDC, respectively, and was not fully restored by incubation with Fe2+. These results show that DEDC and DMDC, but not MDC, are low potency cytotoxins that decrease TH activity in cultured cells through mechanisms other than inhibition of BH4 biosynthesis or iron chelation.
Montine
T J
TJ
Department of Pathology and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Underhill
T M
TM
Valentine
W M
WM
Graham
D G
DG
D000704:Analysis of Variance; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D004125:Dimethyldithiocarbamate / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D016716:PC12 Cells; D051381:Rats; D013859:Thiocarbamates / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors*
D004125:Dimethyldithiocarbamate; D004791:Enzyme Inhibitors; D013859:Thiocarbamates; C008435:methyldithiocarbamate; D001708:Biopterins; D004050:Ditiocarb; D014446:Tyrosine 3-Monooxygenase; C003402:sapropterin