MULTIPLE INTERFERENCES ON CATECHOLAMINE METABOLISM BY TETRAHYDROISOQUINOLINES (TIQS)

ngs are thought to be formed by condensation between dopamine and cert ain metabolites of ethanol, organic solvents and anesthetic gases. Des cribed here are experiments aimed at evaluating ngs interference with catecholamine synthesis. Rat adrenal pheochromocytoma (PC 12) cell lys ates were exposed to benzyl-TIQ and phenyl-TlQ. The activities of tyro sine hydroxylases (TH) and dopamine beta-hydroxylase (DBH) were measur ed by HPLC-based methods following exposure to variable concentrations of TlQs. The effects of TlQs on DBH activity were also assessed in hu man serum. Dixon plot analyses revealed that TlQs act on TH as competi tive inhibitors with different affinity. Ki for benzyl- and phenyl-TlQ were 5 and 3 mu M respectively. DBH activity in serum exposed to benz yl- and phenyl-TlQ ranging from 0.2 to 20 mu M rose respectively by 12 .5% to 58% for benzyl- and by 7.8% to 26% for phenyl-TlQ. Such ngs int erferences with catecholamine metabolism seem to account for dopamine (DA) depletion observed in parallel in vitro experiments on PC12 cells . The dose-dependent inhibition of TH and the increased activity of DB H together with the relatively low effective doses of ngs suggest this mechanism as a possible explanation of the selective toxicity of styr ene and other solvents to dopaminergic systems observed in rabbits fol lowing experimental exposure and suspected to occur in occupationally- exposed workers. (C) 1994 Intox Press, Inc.