Multiple interferences on catecholamine metabolism by tetrahydroisoquinolines (TIQs).
TIQs are thought to be formed by condensation between dopamine and certain metabolites of ethanol, organic solvents and anesthetic gases. Described here are experiments aimed at evaluating TIQs interference with catecholamine synthesis. Rat adrenal pheochromocytoma (PC12) cell lysates were exposed to benzyl-TIQ and phenyl-TIQ. The activities of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) were measured by HPLC-based methods following exposure to variable concentrations of TIQs. The effects of TIQs on DBH activity were also assessed in human serum. Dixon plot analyses revealed that TIQs act on TH as competitive inhibitors with different affinity. Ki for benzyl- and phenyl-TIQ were 5 and 3 microM respectively. DBH activity in serum exposed to benzyl- and phenyl-TIQ ranging from 0.2 to 20 microM rose respectively by 12.5% to 58% for benzyl- and by 7.8% to 26% for phenyl-TIQ. Such TIQs interferences 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 DBH together with the relatively low effective doses of TIQs suggest this mechanism as a possible explanation of the selective toxicity of styrene and other solvents to dopaminergic systems observed in rabbits following experimental exposure and suspected to occur in occupationally-exposed workers.
Laboratory of Industrial Toxicology, University of Parma, Italy.
A
A
Smargiassi
C
C
Biagini
A
A
Mutti
E
E
Bergamaschi
A
A
Bacchini
R
R
Alinovi
S
S
Cavazzini
D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D007546:Isoquinolines / Q000633:toxicity*; D016716:PC12 Cells; D051381:Rats; D044005:Tetrahydroisoquinolines; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors
D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C074266:4-phenyl-1,2,3,4-tetrahydroisoquinoline; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D004298:Dopamine