A Mechanistic Study of S-Adenosyl-L-methionine Protection Against Acetaminophen Hepatotoxicity

Publication Year:
2012

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Repository URL:
http://mds.marshall.edu/etd/347
Author(s):
Brown, James Michael
Tags:
4-Hydroxynonenal; Acetaminophen; Hepatotoxicity; Oxidative Stress; S-Adenosylhomocysteine; S-Adenosyl-L-methionine; Chemicals and Drugs; Medicine and Health Sciences
thesis / dissertation description
Acetaminophen (APAP) toxicity remains the leading cause of drug induced liver failure in the United States. The current therapy for APAP toxicity is N-acetylcysteine (NAC). NAC must be administered within eight hours of APAP overdose for maximum efficacy. That, coupled with the fact that APAP toxicity may not be overtly evident, makes an alternative therapeutic intervention worth exploring. Previous work by our laboratory has demonstrated that S-adenosyl-L-methionine (SAMe) prevents APAP toxicity when given following APAP overdose in C57Bl/6 mice at a level comparable to NAC. The focus of the current work was to examine the mechanistic aspects of this protection in the same mouse model. Male C56Bl/6 mice were randomly allocated into Vehicle (water 15 mL/kg, ip), SAMe (1.25 mmol/kg, ip), APAP (250 mg/kg, ip), and SAMe given one hour after APAP. Mice were fasted the night before experiments and toxicity assessed using liver weight and plasma ALT. Livers were collected from the mice at 2, 4, and 6 hours following APAP administration. Our laboratory then examined levels of SAMe following APAP overdose alone and found that they were depressed by up to 60% and that SAMe given following APAP prevented this drop. Additionally, we demonstrated protection of critical antioxidant pathways by SAMe following APAP overdose. This finding helps explain the previous observation by our laboratory that SAMe prevents an increase in oxidative stress markers following APAP toxicity. We also demonstrated, for the first time, in our model that SAMe prevents oxidative damage in the mitochondria after APAP overdose. However, SAMe was not able to prevent mitochondrial swelling in spite of other signs of mitochondrial protection. Additionally, we also found that SAMe, a known substrate of the polyamine pathway, feeds into this pathway resulting in increased levels of the cytoprotective polyamines spermidine and spermine. Finally, we verified prior findings of an ongoing collaboration with Dr. Serrine Lau, University of Arizona, about 4-hydroxy-2-nonenal (4-HNE) protein adduction following APAP toxicity. I also identified other potential mitochondrial targets of 4-HNE adduction. My results demonstrate that SAMe is very effective as a therapeutic intervention for APAP toxicity in C57Bl/6 mice, an animal model that is known to metabolize APAP similarly to humans. Our findings suggest a mechanism by which SAMe can prevent APAP toxicity.