Interactions of salsolinol with oxidative enzymes

Tyrosinase (EC 1.14.18.1)/O2, ceruloplasmin (human type X)/O2, and peroxidase (EC 1.11.1.7)/H2O2 oxidized the endogenous central nervous system alkaloid salsolinol (SAL) at physiological pH. The proximate oxidation product was an electrophilic ortho-quinone (4) which at pH 7.0 rapidly tautomerized. Four major initial products were formed from 4: cis- and trans-1,2,3,4-tetrahydro-1-methyl-4,6,7-isoquinolinetriol (A and B, respectively), 2,3,4-trihydro-1-methyl-7-hydroxy-6-oxyisoquinoline (C), and 1-methyl-6,7-isoquinoline diol (D). Mechanisms describing the formation of these products have been presented. Ortho-quinone 4, formed in the enzyme-mediated reactions, was rapidly attacked by glutathione to yield the 5-S-, 8-S-, and 5,8-bi-S-glutathionyl conjugates of SAL. Preliminary experiments indicated that injection of A, B and C into the CNS of mice evoked profound behavioral effects. Quinone methide C was toxic. The potential role of the oxidation of salsolinol in the neurodegenerative and behavioral effects associated with chronic alcoholism is discussed.