143 J BIOCHEM MOLECULAR TOXICOLOGY Volume 12, Number 3, 1998 Streptozotocin May Provide Protection against Subsequent Oxidative Stress of Endotoxin or Streptozotocin in Rats Hossam M. Omar, 1 Jason K. Rosenblum, 2 Ruth A. Sanders, 2 and John B. Watkins III 2 1 Zoology Department, Faculty of Science, Assiut University, Assiut, Egypt, 71615; 2 Medical Science Program, Indiana University School of Medicine, Bloomington, IN 47405 Received 18 April 1997; revised 08 August 1997; accepted 22 August 1997 ABSTRACT: Endotoxin lipopolysaccharide (LPS) and streptozotocin-induced diabetes are known to cause oxidative stress in vivo. There is some evidence that a sublethal dose of LPS provides protection against sub- sequent oxidative stress. Because of its wide use as a diabetogenic agent, this study was undertaken to de- termine if streptozotocin can likewise provide a pro- tective effect against further oxidative stress in rats. Female Sprague–Dawley rats were given streptozoto- cin (50 mg/kg intraperitoneally once) prior to exposure to either bacterial endotoxin from Salmonella abortus equii (5 mg/kg intraperitoneally) or three additional daily doses of streptozotocin (50 mg/kg intraperito- neally). One week after LPS or streptozotocin treat- ments, oxidative stress was determined by measuring changes in antioxidant activity (glutathione peroxi- dase, glutathione reductase, superoxide dismutase, cat- alase, glutathione S-transferase, and c-glutamyltran- speptidase) and in concentrations of glutathione, nitrite, and thiobarbituric acid reactants in liver, kid- ney, intestine, and spleen. High levels of some anti- oxidants in the LPS-control and streptozotocin-control rats, in contrast to normal levels found in diabetes  LPS and multidose-streptozotocin rats, suggest that streptozotocin, like LPS, may confer a protective effect against subsequent oxidative stress.  1998 John Wiley & Sons, Inc. J Biochem Toxicol 12: 143–149, 1998 KEY WORDS: Streptozotocin, Lipopolysaccharide, Anti- oxidant, Lipid Peroxidation, Diabetes, Rat, Endotoxin, Oxidative Stress, Free Radical. INTRODUCTION Oxidative stress is a disturbance in the prooxi- dant–antioxidant balance in favor of the former, lead- Address correspondence to John B. Watkins III, Medical Sci- ences Program, Indiana University School of Medicine, Blooming- ton, IN 47405. Telephone: (812) 855-3201; Fax: (812) 855-4436  1998 John Wiley & Sons, Inc. CCC 1095-6670/98/030143-07 ing to potential cellular damage (1). Oxidative damage through the production of free radicals and hydrogen peroxide is a common phenomenon in many destruc- tive biological processes (2) and may follow exposure to various chemical agents (3). Oxidative stress can oc- cur when reactive oxygen intermediates such as free radicals or hydrogen peroxide are formed artificially by UV light, gamma rays, and certain drugs, or as by- products during respiration, inflammation, and hyp- oxia (4). Lipopolysaccharide (LPS), originating from the cell wall of gram-negative bacteria, causes endotoxic shock, resulting in cellular damage due to decreased cardiac output (5). The initial circulatory shock devel- ops as a result of activation of macrophages (6), which generates free radicals (7), such as superoxide, that in- duce oxidative stress (4), lipid peroxidation (8), and increased radical detoxifying capacity (9). Antioxidants afford protection by trapping reac- tive radicals to prevent oxidative stress and cellular damage (10). Such antioxidants include superoxide dismutase (SOD), catalase, glutathione (GSH), GSH peroxidase, GSH reductase, vitamin E, ascorbate, and others, such as lipases, which remove oxidized fatty acids (1). In addition, exposure to a sublethal dose of endotoxin offers protection against subsequent oxida- tive stress (7,11,12), and antioxidants can protect against some endotoxin-induced hepatic damage as well (13,14). The cellular mechanisms involved in gen- erating this protective effect are not completely under- stood. Streptozotocin (STZ) is an antibiotic, chemothera- peutic agent that kills b cells in the pancreas via reac- tive oxygen intermediates (15), which is widely used to create an animal model of insulin-dependent dia- betes. Since diabetes also produces oxidative stress (10), our interest was in determining whether use of the diabetogen prior to administration of a second ox-