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Alternatives to Laboratory Animals - ATLA

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Studies on a-Hexachlorocyclohexane Cytotoxicity, Genotoxicity and Cytochrome P450 Induction in Primary Hepatocytes and Hepatoma Cell Lines from Rodents and Humans

Margherita Ferro, Anna Maria Bassi, Daniela Adamo, Francesca Mattioli, Luigi Robbiano and Giorgio Nanni

α-Hexachlorocyclohexane (α-HCH) was examined for cytotoxicity, genotoxicity and cytochrome P450 induction in primary cultures of mouse, rat and human hepatocytes and in three hepatoma cell lines (Hepa 1c1c7, FaO and Hep G2, from mouse, rat and man, respectively). The cell lines were much more sensitive to the cytotoxicity of the classical inducers phenobarbital and 3-methylcholanthrene than that of α-HCH, whereas no cytotoxicity was observed in primary hepatocytes. Exposure for 24 hours to 0.32mM α-HCH produced a modest, but statistically significant, frequency of DNA breaks, as measured by the alkaline elution assay, in the mouse Hepa 1c1c7 cell line, and the human Hep G2 cell line, but not in the rat FaO cell line. In the Hep G2 cell line, the amount of DNA fragmentation was found to increase with the length of exposure. Compared with the results of previous observations on primary cultures, with regard to species specificity, only the human cell line gave a concordant positive response. Monooxygenase activity induction in primary hepatocytes, despite rather high initial levels of 7-ethoxycoumarin-O-deethylase activity, was low with the classical inducers phenobarbital and 3-methylcholanthrene. α-HCH caused no induction of monooxygenase. The rat FaO and human Hep G2 cell lines were sensitive to α-HCH, but only after long exposure. The results of this study support the hypothesis that α-HCH might act as a weak genotoxic agent in humans, but they also suggest caution in the extrapolation to the in vivo situation of the observations made in established cell lines.