2,3-epoxy-4-hydroxynonanal as a potential tumor-initiating agent of lipid peroxidation

Trans-4-hydroxy-2-nonenal (HNE) is a product of lipid peroxidation. In the presence of t-butyl hydroperoxide the racemic HNE readily converts to its epoxide, 2,3-epoxy-4-hydroxynonanal (EH), as a pair of diastereomers. In this study, the potential roles of HNE and EH as tumor initiating agents were assessed. The mutagenicities of HNE and EH isomers in Salmonella strains TA100 and 104 were examined. In addition, the tumor initiating activities of HNE and EH were evaluated in bioassays involving either topical application in CD-1 mice or i.p. administration in newborn CD-1 mice. In the mutagenicity assays, EH isomers induced similar levels of revertants in both tester strains, although EG isomers were previously shown to react with bases in DNA with different specificity (Sodum, R.S. and Chung, F.-L., Cancer Res., 51, 137-143, 1991). The major isomer induced approximately 20,000 revertants/mumol in TA100 and 15,000 revertants/mumol in TA104, whereas, the minor isomer induced approximately 40,000 revertants/mumol in TA100 and 20,000 revertants/mumol in TA104. HNE was, however, not mutagenic under the assay conditions. In the tumor bioassays, EH was a weak tumorigen in CD-1 mice upon topical application followed by TPA promotion, yielding 0.55 tumors/mouse and 40% tumor incidence at a total dose of 128 mumol/mouse versus 0.02 tumors/mouse and 5% tumor incidence in the control group. Both HNE and EH induced liver tumors in male mice, but not in female mice. However, the incidences were not statistically significant. EH administered i.p. at a total dose of 200 nmol/mouse exacerbated the chronic spontaneous nephropathy in newborn CD-1 mice. Although the incidence of mild nephropathy was comparable in both EH-treated and control groups, the incidence of more severe lesions in mice treated with 200 nmol/mouse was 21%; while it was 0% in the control group. Furthermore, two mice at each dose level of EH showed a tubule profile with complex hyperplastic lining, suggestive of atypical hyperplasia. Again, HNE was not as active as EH in these bioassays. These results suggest a possible role of EH in tumorigenesis associated with lipid peroxidation.