DIMAPRIT ANALOGS INHIBIT TYROSINASE VIA A DISULFIDE BREAKDOWN PRODUCT INDEPENDENTLY OF THE HISTAMINE-H2-RECEPTOR

Histamine displayed specific and saturable binding to membrane fractions of the human melanoma cell line MM96E (K-d = 72.4 nM and B-max = 487 fmol/mg protein). There was weak competition with isothioureas that inhibit tyrosinase in intact cells: dimaprit (an H-2 agonist) nordimaprit and S-[2-(N,N-diisopropyl)ethyl] isothiourea (DINOR). Under culture conditions, rapid, pH-dependent hydrolysis of the isothiureas occurred, with cleavage to urea and a thiol which spontaneously oxidised to the disulphide. The H-3 agonist imetit, which also inhibited tyrosinase, behaved similarly. The disulphide breakdown product of DINOR but not the thiol inhibited tyrosinase activity in intact MM96E cells to a similar extent as DINOR itself. Isothioureas with more bulky substituents, however, were stable in culture and did not inhibit tyrosinase. The results show that (a) certain histaminergic drugs exert effects via a disulphide hydrolysis product independently of the histamine H-2 receptor, and (b) beta-aminoethyldisulphides are depigmenting agents. (C) 1994 Academic Press, Inc.