Inability of methapyrilene to induce sister chromatid exchanges in vitro and in vivo.

The induction of sister chromatid exchanges (SCE) by the hepatocarcinogen methapyrilene hydrochloride was investigated using appropriate in vitro and in vivo mammalian cell systems. Methapyrilene, even at the maximum tolerated dose, did not induce SCE in Chinese hamster ovary cells (CHO) or when CHO cells or hamster lung fibroblasts, V-79, were cocultivated with early cultures of rat liver epithelial cells, which are known to metabolize different classes of chemical carcinogens to active forms. Moreover, a hybrid clone of cells (formed by fusion of CHO cells with rat liver epithelial cells), which is highly sensitive to SCE formation by a number of xenobiotics, failed to produce SCE after treatment with methapyrilene. Experiments in vivo with bone marrow cells and in vitro with CHO cells cocultivated with primary hepatocytes from rats also confirmed the inability of methapyrilene to induce SCE in the indicator cells. Since aflatoxin B1 induced SCE in the in vitro and in vivo models, it may be concluded that methapyrilene does not induce SCE at a concentration which is not cytotoxic to the indicator cells in the different systems described. Autoradiographic studies in cultured rat liver cells with tritiated methapyrilene showed that the label was localized in the cytoplasm but not in the interphase nuclei or in the metaphase chromosomes, indicating a lack of interaction of methapyrilene with the nuclear macromolecules of the putative target cells for methapyrilene.