title: Evaluation of the calcium mobilizing action of acetaminophen and bromobenzene in rat hepatocyte cultures.
abstract: Acetaminophen (APAP) and bromobenzene (BrB) are reported to selectively inhibit plasma membrane (PM) but not endoplasmic reticulum (ER) Ca2+ transport in rat liver (1). The ability of these hepatotoxicants to increase cytoplasmic Ca2+ levels as a result of disrupted Ca2+ pumping was determined in cultured rat hepatocytes by monitoring the activity of glycogen phosphorylase alpha, a Ca2+ -sensitive (via phosphorylase kinase) enzyme. Following exposure to 2.5 to 10 mM APAP for five minutes, dose-dependent increases in phosphorylase alpha activity were observed (58 to 190 U/g protein). Endoplasmic reticulum Ca2+ pump activity was not inhibited after any dose of APAP (56 nmol Ca2+ per milligram protein per 30 minutes). Phosphorylase alpha activity remained elevated for 60 minutes after exposure to APAP (124 microliters/g protein). Following exposure to 0.5 to 2 mM BrB for five minutes, phosphorylase alpha activity also increased (58 to 229 U/g protein) in a dose-related manner. Endoplasmic reticulum Ca2+ pump activity was inhibited after BrB exposure (from 58 to 16 nmol Ca2+ per milligram protein per 30 minutes). Phosphorylase alpha activity remained elevated for 60 minutes after exposure to BrB (147 U/g protein). Evidence of elevated cytoplasmic Ca2+ is consistent with the inhibition of Ca2+ -extruding/sequestering mechanisms at hepatocyte PM and/or ER. Prolonged elevation of cytosolic Ca2+ levels could overstimulate Ca2+ -sensitive processes within liver cells and thus initiate or contribute to hepatotoxic injury.
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
authors.forename: R M
authors.initials: RM
authors.lastname: Long
authors.forename: L
authors.initials: L
authors.lastname: Moore
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D001969:Bromobenzenes / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000032:analysis; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D010762:Phosphorylase a / Q000378:metabolism; D051381:Rats
chemical_list: D001969:Bromobenzenes; D000082:Acetaminophen; D000242:Cyclic AMP; D010762:Phosphorylase a; D002118:Calcium