Cytochrome P4502C11 is a target of diclofenac covalent binding in rats
| Autor: | Sally J. Hargus, Sijiu Shen, Brian M. Martin, Lance R. Pohl |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Male
Diclofenac Cytochrome Toxicology Adduct Substrate Specificity Rats Sprague-Dawley chemistry.chemical_compound Cytochrome P-450 Enzyme System In vivo medicine Animals Cytochrome P-450 Enzyme Inhibitors Enzyme Inhibitors Antiserum chemistry.chemical_classification biology Chemistry Anti-Inflammatory Agents Non-Steroidal General Medicine Glutathione Rats stomatognathic diseases Enzyme Biochemistry Steroid 16-alpha-Hydroxylase Steroid Hydroxylases Microsome biology.protein Microsomes Liver Female Aryl Hydrocarbon Hydroxylases medicine.drug |
| Zdroj: | Chemical research in toxicology. 10(4) |
| ISSN: | 0893-228X |
| Popis: | Diclofenac antiserum was previously developed and used to detect protein adducts of metabolites of dichlofenac in livers of mice and rats. In this study, the antibody has been used to facilitate the purification of a major 51 kDa microsomal adduct of diclofenac from the liver microsomes of male rats that were treated with diclofenac. The adduct was identified as male-specific cytochrome P4502C11 based on its N-terminal amino acid sequence, reaction with a cytochrome P4502C11 antibody, and by its absence from liver microsomes of diclofenac-treated female rats. When diclofenac was incubated with liver microsomes of control rats in the presence of NADPH, only the 51 kDa adduct was produced. The formation of the adduct was inhibited by a cytochrome P4502C11 monoclonal antibody, but not by reduced glutathione or N-alpha-acetyl-L-lysine. No adduct was detected when diclofenac was incubated with liver microsomes from female rats. Moreover, adduct formation in vivo appeared to lead to a 72% decrease in the activity of cytochrome P4502C11. The results indicate that cytochrome P4502C11 metabolizes diclofenac into a highly reactive product that covalently binds to this enzyme before it can diffuse away and react with other proteins. |
| Databáze: | OpenAIRE |
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