title: Effect of oxidative stress by iron on 4-hydroxynonenal formation and proliferative activity in hepatomas of different degrees of differentiation.
abstract: It has been shown previously that oxidative stress by ferrous iron in vitro leads to an inhibition of proliferation of murine ascites tumour cells in vivo. This effect is associated with increased lipid peroxidation in terms of formation of the highly reactive aldehyde 4-hydroxynonenal (HNE), which has been shown to inhibit the proliferation of numerous tumours and to induce differentiation. It was the purpose of this article to study the occurrence and metabolism of HNE and its inducibility by oxidative stress in hepatomas of different degrees of differentiation to find further evidence for a possible role of HNE in proliferation and/or differentiation, because it is known that in hepatoma cells with a very low degree of differentiation basal lipid peroxidation is hardly detectable, while in normal hepatocytes the basal level of thiobarbituric acid reactive substances (TBArS) is rather high. MH1C1 hepatoma cells and Yoshida AH-130 hepatoma cells were chosen as highly differentiated and poorly differentiated tumour cells, respectively, and rat hepatocytes served as a control for normal liver phenotype. Ferrous histidinate (Fe/His) did not have a cytotoxic effect on Yoshida and MH1C1 cells, as measured by the LDH release test. In cell culture studies Fe/His revealed a dose dependent inhibition of the proliferation of Yoshida cells. The incorporation of 3H-thymidine into DNA of these cells was also inhibited by Fe/His in a dose-dependent manner, while the precursor uptake into the cytoplasm was unaffected. The basal levels of HNE were in the order: hepatocytes > MH1C1 cells > Yoshida cells. Both hepatocytes and Yoshida cells responded to the presence of Fe/His with increased formation of TBArS. Compared with hepatocytes the response of the Yoshida cells was greatly reduced. The response of cells to Fe/His with respect to HNE formation was decreased in the order: hepatocytes > MH1C1 cells > Yoshida cells, but in this case the differences were not very pronounced. The metabolic capacity of the cells to consume HNE was also decreased in the order: hepatocytes > MH1C1 cells > Yoshida cells. In this case the differences were very pronounced. These findings support the view that Yoshida cells with a low degree of differentiation and a low basal level of HNE are released from an inhibitory effect of HNE operative in hepatocytes and that HNE is causally involved in the iron induced inhibition of proliferation of poorly differentiated hepatoma cells.
authors.affiliation: Institute of Biochemistry, University of Graz, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Hammer
authors.forename: M
authors.initials: M
authors.lastname: Ferro
authors.forename: H M
authors.initials: HM
authors.lastname: Tillian
authors.forename: F
authors.initials: F
authors.lastname: Tatzber
authors.forename: H
authors.initials: H
authors.lastname: Zollner
authors.forename: E
authors.initials: E
authors.lastname: Schauenstein
authors.forename: R J
authors.initials: RJ
authors.lastname: Schaur
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D002452:Cell Count / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005260:Female; D006639:Histidine / Q000494:pharmacology*; D007501:Iron / Q000494:pharmacology*; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000494:pharmacology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000447:Aldehydes; D004273:DNA, Neoplasm; D009942:Organometallic Compounds; D017392:Thiobarbituric Acid Reactive Substances; C057179:ferrous histidinate; D006639:Histidine; D007501:Iron; D007770:L-Lactate Dehydrogenase; C027576:4-hydroxy-2-nonenal; D013936:Thymidine