CHEMICAL PATHOLOGY OF HOMOCYSTEINE .2. CARCINOGENESIS AND HOMOCYSTEINE THIOLACTONE METABOLISM

Abnormalities of methionine metabolism in malignancy include carcinoge nicity of methionine deficiency, methionine auxotrophy of cultured mal ignant cells, deficient methylation of DNA, and aerobic glycolysis tha t is reversed by methionine. Cells from children with homocystinuria f orm an aggregated sulfated extracellular matrix and grow in a pattern similar to cultured malignant cells. Normal cells metabolize homocyste ine thiolactone to sulfate, but malignant cells accumulate homocystein e thiolactone, which thiolates proteins and other cellular macromolecu les. Thioretinamide, the amide of retinoic acid homocysteine thiolacto ne, and its cobalamin complex, thioretinaco, are antineoplastic and ch emopreventive against carcinogenesis. Deficiency of these compounds in malignant cells is believed to increase conversion of methionine to h omocysteine thiolactone and thioco, its cobalamin complex. These compo unds are believed to participate in oxidative phosphorylation by forma tion of thioretinaco ozonide disulfonium complexes that are the active sites of adenosine triphosphate (ATP) binding in mitochondrial membra nes. Hypothetical deficiency of thioretinaco may explain important met abolic abnormalities of malignant cells.