GENOTOXIC EFFECTS OF SELECTED PEROXISOME PROLIFERATORS

Peroxisome proliferators, a class of structurally dissimilar chemicals including hypolipidemic drugs and industrial plasticizers, have been shown to be associated with hepatocarcinogenesis although an initiating effect could not yet be demonstrated in the cell systems utilized. For this reason the genotoxic potential of the peroxisome proliferators nafenopin, ciprofibrate and di(2-ethylhexyl)adipate (DEHA) was determined in primary cultures of adult rat hepatocytes. To further test if these compounds are genotoxic per se or the genotoxic effect is due to peroxisome proliferation, the cultures were exposed for 3 and 51 h. Treatment for 3 h with the hypolipidemic drugs nafenopin and ciprofibrate induced statistically significant increases of SCE at concentrations greater-than-or-equal-to 30 and 100 muM respectively. At higher concentrations statistically significant increases of chromosomal aberrations (nafenopin: 100 muM; ciprofibrate: greater-than-or-equal-to 100 muM) and micronuclei (ciprofibrate: greater-than-or-equal-to 250 muM) were also found. The presence of peroxisome proliferators in the media until harvesting (51 h) did not significantly alter the dose response of SCE, micronuclei and chromosomal aberration induction by ciprofibrate, while long-term exposure to nafenopin resulted in statistically significant increases of chromosomal aberrations and micronuclei at concentrations greater-than-or-equal-to 30 muM. The differences were statistically significant at 30 and 100 muM for micronuclei, and at 30 muM for chromosomal aberrations. Neither short- nor long-term exposure to DEHA produced a significant genotoxic effect up to 200 muM. The peroxisome proliferators tested were not cytotoxic at any concentration, as determined by mitotic index. These results clearly demonstrate that the peroxisome proliferators nafenopin and ciprofibrate can cause genotoxic effects in primary cultures of adult rat hepatocytes. The comparison of short- and long-term exposure does not suggest a strong correlation between the induction of peroxisome proliferation and genotoxicity, since long-term exposure did not significantly alter the dose response and - except for nafenopin - the extent of the genotoxic effects.