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Molecular Pharmacology, Vol 14, 644-653, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics
1 Department of Pathology, Duke University Medical Center and Gross Chemical Laboratory, Department of
Chemistry, Duke University, Durham, North Carolina 27710
The mechanism of cytotoxicity of 6-hydroxydopamine, 2,4,5-trihydroxyphenylalanine,
dopa, dopamine, norepinephrine, and epinephrine was explored by asking whether cytotoxicity was a reflection of the potential for autoxidation of each polyphenol or of the
sulfhydryl reactivity of its quinone products. The cytotoxicity of the polyphenols, as
measured by inhibition of [3H]thymidine incorporation into DNA by C1300 neuroblastoma cells in tissue culture, correlated with the rate of autoxidation, as measured
spectrophotometrically or by oxygen electrode studies. Polarographic determinations of
the oxidation potentials of the polyphenols were also predictive of cytotoxicity; the most
cytotoxic compounds had the most negative half-wave potentials and thus were the most
readily oxidized. By contrast, the sulfhydryl reactivity of the quinone oxidation products
of the polyphenols, as measured by inhibition of purified calf thymus DNA polymerase
, exhibited an inverse relationship to the cytotoxicity of the polyphenols; the most toxic
compounds, 6-hydroxydopamine and 2,4,5-trihydroxyphenylalanine, were oxidized to the
least reactive quinone products. An alternative mechanism of toxicity was observed with
N-acetyldopamine, which was oxidized to 4-(2-N-acetylaminoethyl)-1,2-benzoquinone, a
potent sulfhydryl reagent. N-Acetyldopamine was more toxic than predicted by its half-wave potential or its rate of autoxidation. Furthermore, while norepinephrine completely
neutralized 6-hydroxydopamine and 2,4,5-trihydroxyphenylalanine as cytotoxic agents,
the toxicity of N-acetyldopamine was minimally affected. Thus we conclude that 6-hydroxydopamine and 2,4,5-trihydroxyphenylalanine kill cells through the production of
H2O2, O2[unknown], and OH·, while for dopamine and dopa the reaction of quinone oxidation
products with nucleophiles probably also contributes to their cytotoxicity.
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