Evaluation of CYP2E1 role in protein nitration, phosphorylation, and endoplasmic reticulum stress in acetaminophen-treated mice

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NIAAA	OXIDSTRESS-1

Authors

• MA Abdelmegeed
• BJ Song

Abstract

We reported that toxic dose of acetaminophen (APAP) nitrotyrosine protein adducts (3-NT) were colocalized with necrotic hepatic centrilobular regions on wild type mice, but not Cyp2e1-null mice where cytochrome P450 2E1 (CYP2E1) is highly expressed, suggesting that CYP2E1 may be essential in mediating 3-NT toxic effect. Herein, we immunopurified cytosolic nitrated proteins in an effort to advance our understanding about their role in APAP-mediated liver toxicity. Mass spectral analysis revealed that some of the proteins of interests included anti-oxidant enzymes and proteins essential in energy production compromising their activities and consequently affecting cell integrity. In addition, we evaluated JNK activation, protein phosphorylation, and ER stress parameters in both wild type and Cyp2e1 null mice, all of which can increase in response to oxidative stress and are well known mediators of APAP-mediated liver toxicity. Indeed, WT mice, but not Cyp2e1 null mice exhibited marked increase in all the parameters examined, suggesting that Cyp2e1 is indeed essential in mediating APAP toxicity in our system and with the dose examined. Whether there is a link between protein nitration, protein phosphorylation and ER stress and if so, whether there is any sequence of events, remain to be seen.

back to top