Role of cellular calcium homeostasis in toxic liver injury induced by the pyrrolizidine alkaloid senecionine and the alkenal trans-4-OH-2-hexenal.
The pyrrolizidine alkaloid senecionine has been shown to be hepatotoxic, genotoxic, and cytotoxic. However, the biochemical mechanism by which senecionine produces hepatocellular toxicity remains to be elucidated. The role of calcium homeostasis in toxic liver injury was examined in isolated rat hepatocytes treated with senecionine and trans-4-OH-2-hexenal (t-4HH), a microsomal metabolite of senecionine, and appropriate cofactors. Hepatocytes treated with senecionine and t-4HH demonstrated greater cytotoxicity (leakage of lactate dehydrogenase) when incubated in the absence of extracellular Ca2+ than in its presence. Both compounds elicited an increase in cytosolic Ca2+ levels of isolated hepatocytes in the presence of extracellular Ca2+. In the following study, senecionine and t-4HH depleted intracellular glutathione levels and induced lipid peroxidation and cytotoxicity in isolated hepatocytes. Pretreatment with the thiol-group reducing agent dithiothreitol prevented depletion of intracellular glutathione and protected hepatocytes against senecionine and t-4HH-induced lipid peroxidation and cytotoxicity. Both compounds also depleted intracellular ATP and NADPH levels. These results suggest that hepatotoxicity induced by senecionine and t-4HH is not dependent on the influx of extracellular Ca2+; however, alterations in intracellular Ca2+, possibly associated with depletion of intracellular glutathione, NADPH, and ATP, may play a critical role.
D000255:Adenosine Triphosphate / Q000032:analysis / Q000378:metabolism; D000447:Aldehydes / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D009249:NADP / Q000032:analysis / Q000378:metabolism; D010762:Phosphorylase a / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D000447:Aldehydes; D011763:Pyrrolizidine Alkaloids; C045934:4-hydroxy-2-hexenal; D009249:NADP; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D010762:Phosphorylase a; D005978:Glutathione; D002118:Calcium