Effects of the pyrrolizidine alkaloid senecionine and the alkenals trans-4-OH-hexenal and trans-2-hexenal on intracellular calcium compartmentation in isolated hepatocytes.
The pyrrolizidine alkaloid senecionine has been shown to produce an increase in cytosolic free Ca2+ concentration in isolated hepatocytes that correlated with an increase in cellular toxicity. The cytotoxicity was greater in the absence of extracellular Ca2+ than in its presence, suggesting that alterations in intracellular Ca2+ distribution, and not an influx of extracellular Ca2+, were responsible for the senecionine-induced hepatotoxicity. The effect of senecionine, as well as the effects of trans-4-OH-2-hexenal (t-4HH), a microsomal metabolite of senecionine, and a related alkenal, trans-2-hexenal, on the sequestration of Ca2+ in mitochondrial and extramitochondrial compartments were examined in isolated hepatocytes. Each of the test compounds elicited a decrease in the available extramitochondrial Ca2+ stores that was inhibited by pretreatment with the thiol group reducing agent, dithiothreitol. Senecionine and t-4HH decreased the level of Ca2+ sequestered in the mitochondrial compartment of hepatocytes. The presence of a pyridine nucleotide reducing agent, beta-hydroxybutyrate, inhibited this reduction. These results suggest that both senecionine and t-4HH inhibit the sequestration of Ca2+ in extramitochondrial and mitochondrial compartments possibly by inactivating free sulfhydryl groups and oxidizing pyridine nucleotides respectively.
Griffin
D S
DS
Department of Pharmacology and Toxicology, School of Veterinary Medicine, University of California, Davis 95616.
Segall
H J
HJ
D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000447:Aldehydes; D000972:Antineoplastic Agents, Phytogenic; D011763:Pyrrolizidine Alkaloids; C045934:4-hydroxy-2-hexenal; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000001:Calcimycin; C051750:2-hexenal; C009237:senecionine; D002118:Calcium; D004229:Dithiothreitol