Received for publication August 9, 2006.
Revised October 23, 2006.
Accepted for publication October 24, 2006.

Comparison of S-Adenosyl-L-methionine and N-acetylcysteine Protective Effects on Acetaminophen Hepatic Toxicity

Abstract

Nutraceuticals are widely used by the general public but very little information is available regarding the effects of nutritional agents on drug toxicity. Excessive doses of acetaminophen (APAP, 4-hydroxyacetanilide) induces hepatic centrilobular necrosis. The naturally occurring substance S-adenosyl-l-methionine (SAMe) has been reported to reduce the hepatic toxicity of acetaminophen (APAP). The present study was designed to investigate the hepatoprotective effects of SAMe in comparison to the clinically used antidote, n-acetylcysteine (NAC). Male C57BL/6 mice were injected intraperitoneal (ip) with an equimolar dose (1.25 mmol/kg) of either SAMe or NAC just prior to APAP and the groups were denoted SAMe+APAP and NAC+APAP, respectively. Mice were immediately injected (ip) with 300 mg/kg APAP and hepatotoxicity was evaluated after 4 h. SAMe was more hepatoprotective than NAC at a dose of 1.25 mmol/kg as liver weight was unchanged by APAP injection in the SAMe+APAP group while liver weight was increased in the NAC+APAP group. SAMe was more hepatoprotective for APAP toxicity than NAC since ALT levels were lower in the SAMe+APAP. Pretreatment with SAMe maintained total hepatic glutathione (GSH) levels higher than NAC pretreatment prior to APAP, although total hepatic GSH levels were lower in the SAMe+APAP and NAC+APAP groups than the vehicle (VEH) control values. Oxidative stress was less extensive in the SAMe+APAP group when compared to the APAP treated mice as indicated by Western blots for protein carbonyls and 4-hydroxynonenal (4-HNE) adducted proteins. In summary, SAMe reduced APAP toxicity and was more potent than NAC in reducing APAP hepatotoxicity.

Key words: N-acetylcysteine, S-adenosyl-L-methionine, acetaminophen toxicity, glutathione, hepatotoxicity, oxidative stress