Experimental and Toxicologic Pathology 64 (2012) 233–237 Contents lists available at ScienceDirect Experimental and Toxicologic Pathology jo u rn al h omepage: www.elsevier.de/etp Protective effect of a cysteine prodrug and antioxidant, L-2-oxothiazolidine-4-carboxylate, against ethanol-induced gastric lesions in rats Meshal Al Moutaery a , Hannan Al Rayes b , Ramaiz Al Swailam b , Ibrahim Elfaki c , Haseeb Ahmad Khan d , Mohammad Arshaduddin c , Mohammad Tariq c,∗ a Prince Sultan Cardiac Center, Armed Forces Hospital, Riyadh, Saudi Arabia b Department of Medicine, Armed Forces Hospital, Riyadh, Saudi Arabia c Research Center, Armed Forces Hospital, Riyadh, Saudi Arabia d Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia a r t i c l e i n f o Article history: Received 10 June 2010 Accepted 15 August 2010 Keywords: Cysteine precursor Anitoxidant Gastric secretion Gastric ulcer Sulfhydryls Myeloperoxidase Glutathione a b s t r a c t Earlier studies have suggested an important role of glutathione (GSH) in cytoprotection against free radicals induced oxidative damage. This study reports gastroprotective effects of a cysteine precursor, L-2-oxothiazolidine-4-carboxylate (OTC), in experimental models of gastric secretion and ulceration. Acid secretion studies (volume and acidity) were undertaken in pylorus-ligated rats whereas the gastric lesions were induced by ethanol. Different groups of animals were treated with OTC (0, 100, 200 and 400 mg/kg). The levels of gastric wall mucus, nonprotein sulfhydryls (NP-SH) and myeloperoxidase (MPO) were measured in the glandular stomach of rats following ethanol-induced gastric lesions. Both medium and high doses of OTC significantly reduced the volume and acidity of gastric secretion in pylorus-ligated rats. Pretreatment with OTC significantly and dose-dependently attenuated the formation of ethanol- induced gastric lesion. OTC significantly protected the gastric mucosa against ethanol-induced depletion of gastric wall mucus, NP-SH and MPO. The gastroprotective effects of OTC may be attributed to its ability to inhibit neutrophils activity and replenish GSH demand. © 2010 Elsevier GmbH. All rights reserved. 1. Introduction The pathogenesis of gastric ulcers is complex, however, numer- ous studies have suggested a key role of reactive oxygen species (ROS) in ulcer formation (Zhu and Kaunitz, 2008; Erbil et al., 2005; Kwiecie ´ n et al., 2002). Drugs with antioxidant properties have shown beneficial effects in alleviating gastric lesions (Dursun et al., 2009; Koc et al., 2008; Sehirli et al., 2008; Suzuki et al., 1998). Glutathione (GSH) is a major cellular antioxidant that protects pro- tein thiols and inhibits cellular damage due to oxygen free radicals (Meister, 1983). GSH plays important roles in antioxidant defense, nutrient metabolism and regulation of cellular events; its defi- ciency contributes to oxidative stress, which plays a key role in the pathogenesis of many diseases (Wu et al., 2004). GSH is abundantly distributed in the mucosal cells of gastrointestinal tract of both ani- mals and humans (Loguercio et al., 1999). A direct relation between GSH concentration and mucosal damage or between GSH-related enzymes and cancer occurrence has been observed in various pathological conditions of the gastrointestinal tract (Loguercio et ∗ Corresponding author at: Research Center, Armed Forces Hospital, P.O. Box 7897 (W-912), Riyadh 11159, Saudi Arabia. E-mail address: rkh research@yahoo.com (M. Tariq). al., 1999). GSH-associated metabolism is a major mechanism for cellular protection against agents which generate oxidative stress (Hayes and McLellan, 1999). Depletion of GSH increases the toxic- ity of many xenobiotics; whereas, treatments with precursors of GSH synthesis such as cysteine, methionine or N-acetylcysteine decrease their toxicity (Meister, 1983). GSH is synthesized from glutamate, cysteine, and glycine in a reaction catalyzed gamma-glutamylcysteine synthetase and GSH synthetase. The cysteine donor, L-2-oxothiazolidine-4-carboxylate (OTC), augments GSH synthesis and has been approved for use in humans. The pharmacokinetics of OTC in healthy volunteers has suggested that OTZ administered intravenously is an efficient means of increasing total blood cysteine (Gwilt et al., 1998). Several clinical studies have shown that OTZ increases blood GSH levels, which improves antioxidant status in these individuals (Moberly et al., 1998; Vita et al., 1998; Bernard et al., 1997). Protective effects of OTC have been observed in experimental nephrotoxicity (Ali et al., 2007; Lee et al., 2006), hepatotoxicity (Iimuro et al., 2000), pulmonary toxicity (Lee et al., 2004; Levy et al., 1998), cardiac dys- function (Poon et al., 1998) and carcinogenicity (Bilbao et al., 2002; Dizdar et al., 2000). In vitro studies have also suggested the anti- inflammatory, antioxidant and cytoprotective effects of OTC (del Olmo et al., 2006; Saberi and Zaree Mahmodabady, 2009; Ferreira et al., 2009; Breborowicz et al., 2004). This investigation was under- 0940-2993/$ – see front matter © 2010 Elsevier GmbH. All rights reserved. doi:10.1016/j.etp.2010.08.012