title: Paracetamol toxicity in hamster isolated hepatocytes: the increase in cytosolic calcium accompanies, rather than precedes, loss of viability.
abstract: Paracetamol is cytotoxic to hamster isolated hepatocytes by a mechanism that does not involve an early increase in [Ca2+]i. Although an increase in [Ca2+]i does occur, it accompanies rather than precedes, loss of viability. Studies with the ionophore, 4-bromo-A23187, suggest that although sustained elevations of [Ca2+]i per se can initiate cell death, this occurs at levels of [Ca2+]i only above 500 nM. This concentration was not achieved on exposure of cells to a cytotoxic concentration of paracetamol for 30 min. The [Ca2+]i-response of hepatocytes to vasopressin stimulation was not altered by exposing the cells to toxic concentrations of paracetamol. This demonstrates that paracetamol does not cause any impairment in the mobilisation or redistribution of Ca2+. The role of elevated levels of [Ca2+]i in mediating chemically-induced cell-killing requires re-evaluation.
authors.affiliation: Department of Clinical Pharmacology, Royal Postgraduate Medical School, University of London, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Hardwick
authors.forename: J W
authors.initials: JW
authors.lastname: Wilson
authors.forename: D J
authors.initials: DJ
authors.lastname: Fawthrop
authors.forename: A R
authors.initials: AR
authors.lastname: Boobis
authors.forename: D S
authors.initials: DS
authors.lastname: Davies
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D000001:Calcimycin / Q000031:analogs & derivatives / Q000737:chemistry; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003600:Cytosol / Q000378:metabolism*; D016257:Fura-2; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008647:Mesocricetus; D014667:Vasopressins / Q000494:pharmacology
chemical_list: D002413:Cations, Divalent; D014667:Vasopressins; D000082:Acetaminophen; D000001:Calcimycin; C033170:4-bromo-A-23187; D002118:Calcium; D016257:Fura-2