GENOTOXIC PROPERTIES OF 4-HYDROXYALKENALS AND ANALOGOUS ALDEHYDES

4-Hydroxynonenal (HNE), one of the major products of lipid peroxidation, has been demonstrated to induce genotoxic effects in the micromolar range. HNE has too structural domains, a lipophilic tail and a polar head with three functional groups: the aldehyde and hydroxy groups and the trans CC double bond. To evaluate their relative importance, the genotoxic effects of HNE were compared with those of the homologous aldehydes 4-hydroxyhexenal and 4-hydroxyundecenal (different lengths of the lipophilic tail), and the analogous aldehydes 2-trans-nonenal (lacking the OH group) and nonanal (lacking the OH group and the trans CC double bond). This investigation was carried out on primary cultures of adult rat hepatocytes in order to further determine the influence of biotransformation- and/or detoxification reactions. A 3-h treatment with HNE induces statistically significant levels of SCE at concentrations greater-than-or-equal-to 0.1 muM, micronuclei at concentrations greater-than-or-equal-to 1 muM and chromosomal aberrations at a concentration of 10 muM. Compared to HNE the homologous aldehydes induced a significant genotoxic effect at higher concentrations. Statistically significant increases in SCE frequency were obtained at concentrations greater-than-or-equal-to 1 muM for 4-hydroxyundecenal and at a concentration of 10 muM for 4-hydroxyhexenal. The induction of chromosomal aberrations was significantly elevated at concentrations of greater-than-or-equal-to 10 muM and 10 muM for 4-hydroxyhexenal and 4-hydroxyundecenal, respectively. Except for a 4-hydroxyhexenal concentration of 1 muM, both aldehydes did not induce statistically significant levels of micronuclei. The HNE analogous aldehydes 2-trans-nonenal and nonanal induced statistically significant frequencies of SCE at concentrations, of greater-than-or-equal-to 1 muM (nonanal) and greater-than-or-equal-to 10 muM (2-trans-nonenal). No significant induction of chromosomal aberrations or micronuclei could be demonstrated. The structure of the aldehydes investigated appears to influence the cyto- and genotoxic potential in the following ways. (1) The length of the lipophilic tail has no influence on chromosomal aberration induction, but appears to determine the yield of SCE and micronuclei, and the cytotoxic potential. (2) The lack of the OH group (2-trans-nonenal) reduces the SCE-inducing potential of the aldehyde shifting the dose-effect curve to higher concentrations. The similar shape compared to SCE induction by HNE indicates that possibly the same active metabolite is formed. (3) The lack of both the OH group and the CC double bond (nonanal) does not result in a complete loss of the SCE-inducing activity. The different shape of the dose-response curve suggests a different metabolism and/or a different mode of interaction with DNA.