Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but at high dose it leads to undesirable side effects, such as hepatotoxicity and nephrotoxicity. The aim of this study was to evaluate the protective role of DDM-GSH, a mixture of L-cysteine, L-methionine, and L-serine in a weight ratio of 2？:？1？:？1, in comparison to N-acetylcysteine (NAC), against acetaminophen- (APAP-) induced hepatotoxicity in mice. Toxicity was induced in mice by the intraperitoneal (ip) administration of low dose (2？mmol/kg) or high dose (8？mmol/kg) of APAP. DDM-GSH (0.4 to 1.6？mmol/kg) was given ip to mice 1？h before the APAP administration. The same was done with NAC (0.9 to 3.6？mmol/kg), the standard antidote of APAP toxicity. Mice were sacrificed 8？h after the APAP injection to determine liver weight, serum alanine aminotransferase (ALT), and total glutathione (GSH) depletion and malondialdehyde (MDA) accumulation in liver tissues. DDM-GSH improved mouse survival rates better than NAC against a high dose of APAP. Moreover, DDM-GSH significantly reduced in a dose-dependent manner not only APAP-induced increases of ALT but also APAP-induced hepatic GSH depletion and MDA accumulation. Our results suggest that DDM-GSH may be more potent than NAC in protecting the liver from APAP-induced liver injury. 1. Introduction Acetaminophen (APAP, 4-hydroxyacetanilide), a nonsteroidal analgesic and antipyretic drug, is used for the treatment of a variety of arthritic and rheumatic conditions with musculoskeletal pain and in other painful disorders such as headache, dysmenorrhea, myalgia, and neuralgia. It is also indicated in conditions accompanied by generalized discomfort or fever, such as common cold and viral infections. APAP is considered to be safe at the therapeutic levels. However, an overdose of APAP in human is fairly common, being yearly in USA the leading cause for calls to Poison Control Centers and accounting for more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths [1]. The APAP overdose is often associated with acute liver failure [1, 2] and renal damage [3] in humans, as well as in experimental animals. At therapeutic doses, APAP is metabolized via glucuronidation and sulfuration reactions occurring primarily in the liver and results in water-soluble metabolites that are excreted renally. As a result of the metabolic conversion of APAP by the microsomal CYP-450 enzyme system, a highly reactive intermediate, N-acetyl-p-benzoquinoneimine (NAPQI), is produced [4]. NAPQI directly reacts with glutathione (GSH), and at
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