okadaic-acid and Chemical-and-Drug-Induced-Liver-Injury

This study was performed to investigate whether okadaic acid (200 ng/kg) produces a protective effect in experimental liver injury induced by intragastric administration of 1000, 2000, and 4000 mg/kg amoxicillin in Sprague-Dawley rats (n=50). The control group was given carboxymethylcellulose sodium solution. Liver injury was assessed by the relative organ weight index, serum ALT activity, and liver malondialdehyde content. Histopathological examination of the liver from rats treated with amoxicillin revealed cell swelling, congestion, apoptosis, and necrosis. The relative liver weight index, ALT activity, and liver malondialdehyde content in these animals were higher than in the control. Administration of okadaic acid reduced the degree of amoxicillin-induced damage to hepatocytes. Thus, okadaic acid can alleviate liver injury caused by amoxicillin.

Topics: Alanine Transaminase; Amoxicillin; Animals; Chemical and Drug Induced Liver Injury; Liver; Malondialdehyde; Okadaic Acid; Rats; Rats, Sprague-Dawley

Simple epithelia express keratins 8 (K8) and 18 (K18) as their major intermediate filament (IF) proteins. One important physiologic function of K8/18 is to protect hepatocytes from drug-induced liver injury. Although the mechanism of this protection is unknown, marked K8/18 hyperphosphorylation occurs in association with a variety of cell stresses and during mitosis. This increase in keratin phosphorylation involves multiple sites including human K18 serine-(ser)52, which is a major K18 phosphorylation site. We studied the significance of keratin hyperphosphorylation and focused on K18 ser52 by generating transgenic mice that overexpress a human genomic K18 ser52--> ala mutant (S52A) and compared them with mice that overexpress, at similar levels, wild-type (WT) human K18. Abrogation of K18 ser52 phosphorylation did not affect filament organization after partial hepatectomy nor the ability of mouse livers to regenerate. However, exposure of S52A-expressing mice to the hepatotoxins, griseofulvin or microcystin, which are associated with K18 ser52 and other keratin phosphorylation changes, resulted in more dramatic hepatotoxicity as compared with WT K18-expressing mice. Our results demonstrate that K18 ser52 phosphorylation plays a physiologic role in protecting hepatocytes from stress-induced liver injury. Since hepatotoxins are associated with increased keratin phosphorylation at multiple sites, it is likely that unique sites aside from K18 ser52, and phosphorylation sites on other IF proteins, also participate in protection from cell stress.

Topics: 3T3 Cells; Actin Cytoskeleton; Amino Acid Substitution; Animals; Chemical and Drug Induced Liver Injury; Genetic Predisposition to Disease; Griseofulvin; Hepatectomy; Humans; Intermediate Filaments; Keratins; Liver Regeneration; Mice; Mice, Transgenic; Microcystins; Okadaic Acid; Peptides, Cyclic; Phosphorylation; Point Mutation; Protein Processing, Post-Translational