| pubmed-article:1680932 | pubmed:abstractText | In cultured human melanoma cells, histamine H1 (mepyramine) and H2 receptor antagonists (cimetidine, ranitidine, impromidine) increased tyrosinase activity, whereas H2 agonists (dimaprit, nordimaprit) decreased activity. Mixtures of agonist and antagonist either decreased or increased tyrosinase activity, depending on the relative concentrations of each drug. Nordimaprit, the most effective inhibitor, lowered tyrosinase activity significantly within 36 h and caused a slower loss of tyrosinase protein as judged by reactivity with two monoclonal antibodies. Prolonged treatment of a melanotic cell line with nordimaprit led to complete loss of pigment, with no loss of the 56-kDa melanosomal antigen 1C11. Cells remained amelanotic for 8 weeks after removal of the drug and, even after 26 weeks, melanin content and tyrosinase expression and activity had not fully recovered. Nordimaprit increased the rate of degradation of tyrosinase and of nordimaprit binding proteins. Whereas nordimprit did not directly inhibit tyrosinase, lysates of treated cells contained an inhibitory activity that partitioned approximately equally across a 10-kDa ultrafiltration membrane. Overall, these results showed that melanogenesis can be controlled via histamine receptors, the mechanism for the H2 agonist nordimaprit consisting of three components: induction of a tyrosinase inhibitor, increased degradation of tyrosinase, and long-term down-regulation of tyrosinase expression. | lld:pubmed |
