Calcium-dependent DNA damage and adenosine 3',5'-cyclic monophosphate-independent glycogen phosphorylase activation in an in vitro model of acetaminophen-induced liver injury

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
V M Salas, G B Corcoran

Abstract

Acetaminophen (N-acetyl-p-aminophenol [APAP]) hepatotoxicity is a process characterized by Ca2+ deregulation. Cellular functions utilizing Ca2+ as a second messenger molecule affect both cytosolic and nuclear signal transduction. Many studies have independently shown Ca2+-related effects on target molecules in response to toxic doses of APAP; however, the primary Ca2+ target resulting in liver necrosis has not been determined. We hypothesize that Ca2+-dependent DNA damage is a critical event in liver necrosis caused by alkylating hepatotoxins. In this study, Ca2+-dependent endonuclease activity was determined from DNA single-strand lesions measured by fluorometric analysis of DNA unwinding. The status of cytosolic Ca2+ was determined by measuring Ca2+-dependent activation of glycogen phosphorylase a. Primary cultures of mouse hepatocytes exposed to a toxic concentration of APAP showed twofold and greater increases in glycogen phosphorylase a stimulation at 6 hours, which was reversible with Ca2+-chelating agents. Cell death was preceded by a large decline in intact, double-stranded DNA. Following toxic administration of APAP, the percentage of total double-stranded DNA was significantly reduced by 2 hours. At 6 and 24 hours, ge...Continue Reading

Citations

Mar 27, 2001·Biochemical and Biophysical Research Communications·T P ReillyL R Pohl
Feb 7, 2013·Cell Communication and Signaling : CCS·Sylvia S AmaralGustavo B Menezes
Apr 1, 2008·Ageing Research Reviews·Craig S Atwood, Richard L Bowen
Jun 1, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Amanda LoGuidice, Urs A Boelsterli
Nov 4, 2004·Chemico-biological Interactions·Patricia E GaneyRobert A Roth
Mar 31, 2016·Scientific Reports·Prashant RaiVincent T K Chow
Apr 3, 2002·Experimental and Toxicologic Pathology : Official Journal of the Gesellschaft Für Toxikologische Pathologie·Irena ManovTheodore C Iancu
Oct 23, 2004·Drug Metabolism and Pharmacokinetics·Takumi IshidaHideyuki Yamada
Jul 29, 2016·World Journal of Gastroenterology : WJG·Mhairi C DonnellyKenneth J Simpson
Nov 20, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Laura P JamesJack A Hinson
May 16, 2001·American Journal of Physiology. Gastrointestinal and Liver Physiology·E WatersD Bouchier-Hayes

❮ Previous
Next ❯

Related Concepts

Related Feeds

Calcium & Bioenergetics

Bioenergetic processes, including cellular respiration and photosynthesis, concern the transformation of energy by cells. Here is the latest research on the role of calcium in bioenergetics.