RT Journal Article
SR Electronic
T1 Melanosome binding and oxidation-reduction properties of synthetic L-dopa-melanin as in vitro tests for drug toxicity.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 470
OP 476
VO 33
IS 4
A1 I Debing
A1 A P Ijzerman
A1 G Vauquelin
YR 1988
UL http://molpharm.aspetjournals.org/content/33/4/470.abstract
AB Fifteen drugs were assessed for their ability to interact with calf eye melanosomes and to inhibit synthetic L-DOPA-melanin-catalyzed oxidation-reduction reactions. All drugs were able to bind to calf eye melanosomes. The Scatchard plots of the saturation binding data were curvilinear. At a free drug concentration of 0.1 mM, binding ranged between 0.8 nmol/mg for pirenzepine and 71 nmol/mg for chloroquine, a compound which has been described as provoking toxic side-effects in melanin-containing tissues and adjacent structures. As a result of its electron transfer properties, synthetic L-DOPA melanin catalyzes the NADH oxidation/ferricyanide reduction reaction. Except for (-)-norepinephrine, which underwent rapid oxidation in the presence of ferricyanide, all of the investigated drugs were also able to inhibit this catalytic activity of L-DOPA-melanin. The degree of inhibition is dictated by the extent of binding rather than by the chemical nature of the drug itself. Chlorpromazine itself was able to catalyze the oxidation-reduction reaction and has been proposed to shunt normal electron transport sequences in vivo. The implications of melanin binding with respect to drug toxicity are discussed in the light of the present observations.