STUDIES ON ALPHA-HEXACHLOROCYCLOHEXANE CYTOTOXICITY, GENOTOXICITY ANDCYTOCHROME-P450 INDUCTION IN PRIMARY HEPATOCYTES AND HEPATOMA-CELL LINES FROM RODENTS AND HUMANS

alpha-Hexachlorocyclohexane (alpha-HCH) was examined for cytotoxicity, genotoxicity and cytochrome P450 induction in primary cultures of mou se, rat and human hepatocytes and in three hepatoma cell lines (Hepa 1 c1c7, FaO and Hep G2, from mouse, rat and man, respectively). The cell lines were much more sensitive to the cytotoxicity of the classical i nducers phenobarbital and 3-methylcholanthrene than that of alpha-HCH, whereas no cytotoxicity was observed in primary hepatocytes. Exposure for 24 hours to 0.32mM alpha-HCH produced a modest, but statistically significant, frequency of DNA breaks, as measured by the alkaline elu tion assay, in the mouse Hepa 1c1c7 cell line, and the human Hep G2 ce ll line, but not in the rat FaO cell line. In the Hep G2 cell line, th e amount of DNA fragmentation was found to increase with the length of exposure. Compared with the results of previous observations on prima ry cultures, with regard to species specificity, only the human cell l ine gave a concordant positive response. Monooxygenase activity induct ion in primary hepatocytes, despite rather high initial levels of 7-et hoxycoumarin-O-deethylase activity, was low with the classical inducer s phenobarbital and 3-methylcholanthrene. alpha-HCH caused no inductio n of monooxygenase. The rat FaO and human Hep G2 cell lines were sensi tive to alpha-HCH, but only after long exposure. The results of this s tudy support the hypothesis that alpha-HCH might act as a weak genotox ic agent in humans, but they also suggest caution in the extrapolation to the in vivo situation of the observations made in established cell lines.