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J. Biol. Chem., Vol. 281, Issue 52, 40485-40492, December 29, 2006

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Menadione-induced Reactive Oxygen Species Generation via Redox Cycling Promotes Apoptosis of Murine Pancreatic Acinar Cells^*

David N. Criddle¹, Stuart Gillies, Heidi K. Baumgartner-Wilson, Mohammed Jaffar^¶, Edwin C. Chinje^¶, Sarah Passmore^¶, Michael Chvanov, Stephanie Barrow, Oleg V. Gerasimenko, Alexei V. Tepikin, Robert Sutton^||, and Ole H. Petersen²

From the MRC Secretory Research Group, Department of Physiology and ^||Division of Surgery and Oncology, University of Liverpool, Liverpool L69 3BX, United Kingdom, Morvus Technology Ltd., Porton Down Science Park, Salisbury, Wiltshire SP4 0JQ, United Kingdom, and the ^¶Department of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, United Kingdom

Oxidative stress may be an important determinant of the severity of acute pancreatitis. One-electron reduction of oxidants generates reactive oxygen species (ROS) via redox cycling, whereas two-electron detoxification, e.g. by NAD(P)H:quinone oxidoreductase, does not. The actions of menadione on ROS production and cell fate were compared with those of a non-cycling analogue (2,4-dimethoxy-2-methylnaphthalene (DMN)) using real-time confocal microscopy of isolated perfused murine pancreatic acinar cells. Menadione generated ROS with a concomitant decrease of NAD(P)H, consistent with redox cycling. The elevation of ROS was prevented by the antioxidant N-acetyl-L-cysteine but not by the NADPH oxidase inhibitor diphenyliodonium. DMN produced no change in reactive oxygen species per se but significantly potentiated menadione-induced effects, probably via enhancement of one-electron reduction, since DMN was found to inhibit NAD(P)H:quinone oxidoreductase detoxification. Menadione caused apoptosis of pancreatic acinar cells that was significantly potentiated by DMN, whereas DMN alone had no effect. Furthermore, bile acid (taurolithocholic acid 3-sulfate)-induced caspase activation was also greatly increased by DMN, whereas DMN had no effect per se. These results suggest that acute generation of ROS by menadione occurs via redox cycling, the net effect of which is induction of apoptotic pancreatic acinar cell death. Two-electron detoxifying enzymes such as NAD(P)H:quinone oxidoreductase, which are elevated in pancreatitis, may provide protection against excessive ROS and exert an important role in determining acinar cell fate.

Received for publication, August 11, 2006 , and in revised form, October 31, 2006.

^* This work was supported by Medical Research Council Program Grant G8801575. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² A Medical Research Council Research Professor.

¹ To whom correspondence should be addressed. Tel.: 44-1517945304; Fax: 44-1517945327; E-mail: criddle{at}liverpool.ac.uk.

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