Lipid peroxidation and cellular damage caused by the pyrrolizidine alkaloid senecionine, the alkenal trans-4-hydroxy-2-hexenal, and related alkenals

Abstract

Lipid peroxidation was examined as a possible mechanism for cell injury by trans-4-OH-2-hexenal, the macrocyclic pyrrolizidine alkaloid senecionine and related alkenals in isolated rat hepatocytes. Each compound elicited a positive dose response for peroxidation of cellular lipids as measured by the formation of thiobarbituric acid-reactive products. The addition of the anti-oxidant N,N'-diphenyl-p-phenylenediamine to the hepatocyte suspensions inhibited the production of thiobarbituric acid-reactants. However, the presence of the anti-oxidant had no protective effects on the cell membrane integrity as evidenced by the leakage of lactate dehydrogenase from the cells into the surrounding media. These results suggest that lipid peroxidation which occurs in the presence of senecionine, trans-4-OH-2-hexenal or related alkenals is not entirely responsible for the cellular damage in isolated rat hepatocytes.

Metabolomic and Genomic Evidence for Compromised Bile Acid Homeostasis by Senecionine, a Hepatotoxic Pyrrolizidine Alkaloid

“…Hydroxyeicosatetraenoic acid showed the largest VIP value at ESI– mode. Hydroxyeicosatetraenoic acid is reportedly associated with liver injury caused by lipid peroxidation, , which is also responsible for PA-induced hepatotoxicity. − , LPCs and bile acids can be detected in both ESI+ and ESI– modes. LPCs ionize much better in ESI+ mode, whereas bile acids form deprotonated ions in ESI– mode more easily.…”

“…This alkaloid is one of the most commonly studied hepatotoxic and tumorigenic PAs. Senecionine exists in over 50 plant species, such as Senecio vulgaris and Gynura segetum , which cause several human intoxications. ,, Substantial research has revealed that senecionine-induced hepatotoxicity is associated with lipid peroxidation, intracellular Ca 2+ alteration, and intercellular glutathione depletion. − However, these processes are not entirely responsible for cellular damage, and the mechanisms through which senecionine induces hepatotoxicity are not exclusively elucidated. In the present study, a universal metabolomics method based on liquid chromatography–mass spectrometry (LC–MS) technology and whole genome microarray was established for nontargeted study of senecionine-induced hepatotoxicity in Sprague–Dawley rats.…”

Role of cellular calcium homeostasis in toxic liver injury induced by the pyrrolizidine alkaloid senecionine and the alkenal trans‐4‐OH‐2‐hexenal

“…Lipid peroxidation may also play an indirect role in the oxidation of pyridine nucleotides in hepatocytes incubated with senecionine and t-4HH. Both senecionine and t-4HH have been shown to produce a dose-related increase in lipid peroxidation in isolated hepatocytes (12). Hydrogen peroxide is generated as a result of this process.…”

“…Peroxidation of polyunsaturated fatty acids present in the membrane lipids was one (11). However, results of recent studies with senecionine in isolated hepatocytes pretreated with the antioxidant N,N'-diphenyl-p-phenylenediamine have suggested that the process of lipid peroxidation and cellular toxicity can be dissociated (12). Accumulation of intracellular Ca2+ ions resulting from the influx of extracellular Ca2+ (13) has also been suggested as a possible mechanism.…”

Japanese Butterbur (Petasites japonicus) Leaves Increase Hepatic Oxidative Stress in Male Rats

“…There is limited information on the oxidative stress induced by unpurified Japanese butterbur, but Segall et al 41) suggested that trans-4-hydroxy-2-hexenal (t-4HH) of reactive metabolites from senecionine of the retronecine type can cause lipid peroxidation in hepatic microsomal lipids. 42) Their follow-up study 43) revealed that senecionine and t-4HH increased the formation of thiobarbituric acid-reactive products in isolated rat hepatocytes. Additionally, Guarnieri and Muscari 44) found elevation of superoxide production and the malondiadehyde concentration in the cardiac muscle of monocrotaline-treated rats.…”