Covalent binding of reactive estrogen metabolites to microtubular protein as a possible mechanism of aneuploidy induction and neoplastic cell transformation.

Neoplastic cell transformation induced by estrogens and some other carcinogens such as benzene appears to involve the induction of mitotic aneuploidy rather than DNA damage and point mutations. As metabolic activation may also play an important role in the mechanism of carcinogenesis of these nongenotoxic compounds, we have studied the interaction of reactive quinone metabolites of various estrogens and of benzene with the major microtubular protein, tubulin, in a cell-free system. Covalent binding of the radioactively labeled metabolites to the alpha- and beta-subunit of tubulin was found to depend on the structure of the metabolite. When the adducted tubulins were tested in vitro for their ability to polymerize to microtubules, inhibition of microtubule assembly was observed in every case, although to varying extents. It is proposed that the formation of covalent tubulin adducts may impair the formation of mitotic spindles and thus contribute to chromosomal nondisjunction and aneuploidy induction.