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Melanogenesis in Human Melanomas¹

Department of Biology, Wayne State University,² Detroit, Michigan 48202

A number of biochemical aspects of melanogenesis were studied in 15 variously melanized human melanomas. The tyrosinase activity was correlated with the degree of melanization: total tyrosinase activity in melanotic melanoma varied from 3,667 to 46,183 tyrosinase units, in partially melanotic melanoma it varied from 168 to 508 tyrosinase units, and in amelanotic melanoma, from 14 to 75 tyrosinase units. The subcellular distribution of tyrosinase activity was limited to the particulate fraction (144,000 x g) of the partially melanotic and amelanotic melanomas. However, the melanotic melanomas contained the enzyme in both particulate and soluble fractions, with the greater tyrosinase activity in the particulate fraction.

Electrophoretic resolution of tyrosinase isozymes in the soluble fraction or lipase-solubilized tyrosinase derived from the particulate fraction revealed three isozymes in melanotic melanomas. The isozyme of intermediate mobility always was the dominant form. In partially melanotic melanomas, the solubilized tyrosinase showed six isozymes. Three were similar to those of melanotic melanomas. The remaining three isozymes showed slower mobilities, possibly with greater molecular weights than the isozymes derived from melanotic melanomas.

Inhibitors of tyrosinase were present in melanomas. Increased tyrosinase activity occurred after storing the homogenate at 0–4°, removing of supernatant from the homogenate sediment, and washing the 144,000 x g particulate fraction, which suggested the presence of water-soluble, loosely bound inhibitor(s) in the soluble fraction of partially melanotic melanoma. Another inhibitor was released from the 144,000 x g particulate fraction of melanotic melanoma after lipase digestion. These substances inhibit both the isolated dominant tyrosinase isozyme (human) and mushroom tyrosinase. As inhibition of tyrosinase activity may produce regression of abnormal cell growth, the inhibitors may provide an approach to melanoma chemotherapy.

¹ This investigation was supported by USPHS Research Grants CA-12731-02 and CA-15991-01 from the National Cancer Institute.

² Contribution No. 318, Department of Biology.

Received 7/16/74. Accepted 11/20/74.