Original ContributionInhibition of hepatic mitochondrial aldehyde dehydrogenase by carbon tetrachloride through JNK-mediated phosphorylation
Section snippets
Chemicals and other materials
NAD+, propionyl aldehyde, pyrazole, and calf intestine alkaline phosphatase were purchased from Sigma (St. Louis, MO, USA). Specific antibodies to c-Jun, phospho-c-Jun (Ser63), JNK, phospho-JNK, phospho-Ser–Pro, or phospho-Thr–Pro were purchased from Cell Signaling Technology (Beverly, MA, USA). Specific monoclonal antibody to mitochondrial ALDH2 was obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Recombinant JNK (Cat. No. 420105) was purchased from Calbiochem (San Diego, CA, USA).
Hepatic damage and oxidative stress after CCl4 exposure
To assess hepatocellular damage in CCl4-exposed rat liver, liver histopathology analysis was performed. H&E staining data showed that normal liver histology was observed in untreated controls and rats exposed to CCl4 for 2 and 4 h. However, marked hepatocyte ballooning and necrosis in the centrilobular region were observed in 16-h CCl4-exposed rat liver (Fig. 1A). Consistent with the histological data, the level of cytochrome c detected in the cytoplasm [31] was markedly elevated at 16 h after
Discussion
Mitochondrial ALDH2 is involved in the metabolism of carbonyl compounds with a very low Km for acetaldehyde and other lipid aldehydes, which are highly reactive and toxic. ALDH2 is known to be inhibited by many chemicals such as disulfiram, HNE, MDA, acetaminophen, ecstasy (3,4-methylenedioxymethamphetamine), and CCl4 [6], [7], [9], [37], [44], [45]. Its activity is also decreased in many pathological conditions such as alcoholic fatty liver, hepatic cancer, aging, and hepatic
Acknowledgments
This research was supported by the Intramural Research Program of National Institute on Alcohol Abuse and Alcoholism. We are grateful to Drs. Klaus Gawrisch and Insong James Lee for support and critical reading of the manuscript, respectively. The authors are also thankful to Dr. Jae-Young Lee, DongKuk University, Seoul, Korea for preparation and analysis of the structural model of ALDH2 protein. Preliminary results of this work were presented at the 13th Carbonyl Meeting in 2006.
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