DIALKYLDITHIOCARBAMATES INHIBIT TYROSINE-HYDROXYLASE ACTIVITY IN PC12CELLS AND IN FIBROBLASTS THAT EXPRESS TYROSINE-HYDROXYLASE

Dithiocarbamates and CS2 have been associated with neurobehavioural ch anges suggestive of central dopaminergic dysfunction. Diethyldithiocar bamate (DEDC), dimethyldithiocarbamate (DMDC), and methyldithiocarbama te (MDC) were examined for their ability to inhibit tyrosine hydroxyla se (TH) activity in PC12 cells and transfected CHO fibroblasts that ex pressed 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 less than or equal to 100 mu M for 18 h; the EC50 for each compound was approximately 5 mM in both cell lines. In c ontrast, the EC50 for MDC was 41 or 74 mu M in PC12 or CHO/TH cultures , respectively. There was no change in immunodetectable levels of TH i n PC12 or CHO/TH cells following exposure to subcytotoxic concentratio ns of dithiocarbamates. DEDC and DMDC (5 to 100 mu M) produced concent ration-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 w as 80.2 +/- 3.4% or 82.4 +/- 2.9% of control following exposure to 100 mu M DEDC or DMDC, respectively, and was not fully restored by incuba tion with Fe2+. These results show that DEDC and DMDC, but not MDC, ar e low potency cytotoxins that decrease TH activity in cultured cells t hrough mechanisms other than inhibition of BH4 biosynthesis or iron ch elation. (C) 1995 Academic Press Limited