Since previous investigations on the genotoxicity of 4-hydroxynonenal (HNE) were carried out with prokaryotic systems or eukaryotic cell lines which may not adequately reflect the response of cells in vivo due to differences in the metabolism, the genotoxic potential of HNE was further evaluated in primary cells (hepatocytes) and cell clones of cerebral endothelial cells expressing specific functions, i.e. blood-brain barrier (BBB) and capillary formation associated phenotypes. Treatment of hepatocytes with HNE induced statistically significant levels of SCE at concentrations >/=0.1 microM, micronuclei at concentrations >/=1 microM and chromosomal aberrations at a concentration of 10 microM. Treatment of cloned cerebral microvascular endothelial cells induced significantly elevated levels of chromosomal aberrations at concentrations >/=1 microM and micronuclei at concentrations >/=10 microM in both cEC phenotypes, compared to the controls. Additionally, cytotoxicity was observed at a concentration of 50 microM HNE and was significantly higher in type II cells. These results indicate that cells expressing differentiated functions representative for the in vivo situation react more sensitive to HNE than cell lines, and may reflect the sensitivity of the target cells. The different response with respect to the endpoints of genotoxicity tested most probably depends on the different metabolizing capacities and thus the action of different metabolites of HNE.