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Biomedical subjects

S P Adams

Publications and source records attributed to S P Adams.

At least 37 records · Page 2Linked to original sources
PubMed1999

Inhibition of isoniazid-induced hepatotoxicity in rabbits by pretreatment with an amidase inhibitor.

Isoniazid (INH), a widely used drug in the prophylaxis and treatment of tuberculosis, is associated with a 1 to 2% risk of severe and potentially fatal hepatotoxicity. There is evidence that the INH metabolite hydrazine plays an important role in the mechanism of this toxicity. Metabolism of INH leads to the production of hydrazine via both direct and indirect pathways. In both cases, the activity of an INH amidase is required to hydrolyze an amide bond. In the present study, using a model of INH-induced hepatotoxicity in rabbits, pretreatment of rabbits with the amidase inhibitor bis-p-nitrophenyl phosphate 30 min before injection of INH inhibited the formation of INH-derived hydrazine and decreased measures of hepatocellular damage, hepatic triglyceride accumulation, and hypertriglyceridemia. Bis-p-nitrophenyl phosphate also potently inhibited the production of hydrazine from INH in in vitro microsomal incubations (IC50 2 microM). Although hepatic glutathione stores are decreased, they are not depleted in animals with INH-induced hepatotoxicity. Significant effects on hepatic microsomal cytochrome P-450 1A1/2 and cytochrome P-450 2E1 activities suggest that these isozymes may be involved in the mechanism of the toxicity. In conclusion, this study demonstrates the importance of amidase activity in this rabbit model of hepatotoxicity and provides additional evidence in support of the role of hydrazine in the mechanism of INH-induced hepatotoxicity.

Amidohydrolases↗
PubMed1998

Identification of ligand binding sites on integrin alpha4beta1 through chemical cross-linking.

We have used chemical cross-linking to identify sequences in integrin alpha4beta1 that are involved in its interactions with ligands. A recently described leucine-aspartic acid-valine (LDV)-based small molecule inhibitor of alpha4beta1 (BIO-1494), that contained a single reactive amino group for targeting the cross-linking, was used for these studies. The specificity of the interaction was defined by (i) the ability to block the interaction with a competitive inhibitor lacking the reactive group, (ii) the absolute requirement of divalent cations for cross-linking, and (iii) the lack of cross-linking to the functionally related integrin alpha4beta7. With ANB-NOS as the cross-linker, only the beta1 chain was labeled with BIO-1494, while with the more flexible cross-linker DSS both the alpha4 and beta1 chains were modified. Similar results were obtained when cross-linking was performed on K562 cells expressing alpha4beta1 but not on K562 cells expressing alpha2beta1. The site of cross-linking on the beta1 chain was localized by CNBr peptide mapping within residues 130-146, a region that contains the putative metal binding site DXSXS and for which analogous data had been generated with RGD binding to integrin alphaIIbbeta3. The striking similarity between the data we generated for an LDV ligand and published data for the RGD family supports the notion of a common ligand binding pocket formed by both integrin chains. The cross-linking strategy developed here should serve as a useful tool for studying alpha4beta1 function.

Amino Acid Sequence↗
PubMed1998

The role of l-thyroxine and hepatic reductase activity in isoniazid-induced hepatotoxicity in rabbits.

There is evidence that hydrazine, a metabolite of isoniazid, plays an important role in the mechanism of isoniazid-induced hepatotoxicity. Hydrazine has been reported to be metabolised by NADPH cytochrome P-450 reductase (reductase) to reactive and potentially toxic intermediates. The present study was designed, using a model of isoniazid-induced hepatotoxicity in rabbits, to determine whether or not reductase plays a role in this toxicity. Although pretreating rabbits with l-thyroxine increased hepatic reductase activity (54% greater than controls), the severity of isoniazid-induced hepatic cell damage (plasma argininosuccinic acid lyase activity) was lower in thyroxine pre-treated animals than in animals treated with isoniazid alone (31.3+/-20 vs 56.0+/-20 Takahara Units, respectively). In addition, pre-treatment with l-thyroxine completely prevented isoniazid-induced hepatic steatosis. In conclusion, contrary to our hypothesis, an increase in reductase activity achieved by pre-treatment with l-thyroxine was associated with a decrease in the severity of isoniazid-induced hepatic cell damage and steatosis in rabbits.

Animals↗