EFFECT OF PHENOTHIAZINES ON MELANOMA TYROSINASE ACTIVITY

¹ Departments of Internal Medicine and Pharmacology, Yale University School of Medicine, New Haven, Connecticut

Chronic chlorpromazine (CPZ) administration was demonstrated to increase the tyrosinase activity in the B-16 melanoma in vivo. In vitro, 10^-3 M CPZ produced a 2-fold increase in the B-16 melanoma tyrosinase and a 50% increase in Harding-Passey melanoma tyrosinase. Other phenothiasine compounds also activated melanoma tyrosinase. Substituents in position 2 in the phenothiasine ring showed the following order of potency for activating tyrosinase: CF₃ > Cl > H. At position 10 of phenothiasine a piperazinoalkyl side chain was more effective in increasing tyrosinase activity than an aliphatic amine. The activation of melanoma tyrosinase by CPZ was greatest in the melanosomal fraction of the melanocyte. Digitonin or a non-ionic detergent, Igepal CO-630, eliminated the increase in melanoma tyrosinase induced by CPZ. CPZ appears to increase melanoma tyrosinase activity by an indirect mechanism, probably related to changes in melanosomal membrane permeability. CPZ did not activate mushroom tyrosinase, serum tyrosinase from melanoma-bearing mice or rat adrenal tyrosine hydroxylase; inhibition of these soluble enzymes occurred in the presence of high concentrations of CPZ. CPZ also increased the incorporation of C¹⁴-dopa into the B-16 melanoma in vivo.