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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Oxidative DNA damage and cytotoxicity induced by copper-stimulated redox cycling of salsolinol, a neurotoxic tetrahydroisoquinoline alkaloid.

A series of neurotoxic tetrahydroisoquinoline alkaloids has been detected in certain regions of mammalian brains. One such dopaminergic tetrahydroisoquinoline neurotoxin is salsolinol (SAL), which is suspected of being associated with the etiology of Parkinson's disease and neuropathology of chronic alcoholism. In the present study, we found that SAL in combination with Cu(II) induced strand scission in pBR322 and phiX174 supercoiled DNA, which was inhibited by the copper chelator, reactive oxygen species (ROS) scavengers, reduced glutathione, and catalase. SAL in the presence of Cu(II) caused hydroxylation of salicylic acid to produce 2,3- and 2,5-dihydroxybenzoic acids. Reaction of calf thymus DNA with SAL plus Cu(II) resulted in substantial oxidative DNA damage as determined by 8-hydroxydeoxyguanosine (8-OH-dG) formation. Blockade of the dihydroxy functional group of SAL abolished its capability to yield 8-OH-dG in the presence of Cu(II). The dehydro analog of SAL, 1-methyl-6,7-dihydroxy-3,4-dihydroisoquinoline, produced significantly high levels of 8-OH-dG when incubated with calf thymus DNA, even in the absence of Cu(II), which appears to be attributable to the tautomer formation by this compound. In another experiment, SAL exerted cytotoxicity when treated to rat pheochromocytoma (PC12) cells. Based on these findings, it seems likely that SAL undergoes redox cycling in the presence of Cu(II) with concomitant production of ROS, particularly hydroxyl radical, which could contribute to DNA damaging and cytotoxic properties of this neurotoxin.[1]

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