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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 23, 2006; DOI: 10.1124/jpet.106.103713

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Received for publication February 28, 2006.
Revised May 18, 2006.
Accepted for publication May 22, 2006.

Biotransformation of glyceryl trinitrate by rat hepatic microsomal glutathione S-transferase 1

Yanbin Ji 1 Brian M Bennett 1*

1 Queen's University

* Address correspondence to: E-mail: bennett{at}post.queensu.ca

Abstract

Although the biotransformation of organic nitrates by the cytosolic glutathione Stransferases (GSTs) is well known, the relative contribution of the microsomal GST (MGST1) to nitrate biotransformation has not been described. We therefore compared the denitration of glyceryl trinitrate (GTN) by purified rat liver MGST1 and cytosolic GSTs. Both MGST1 and cytosolic GSTs catalyzed the denitration of glyceryl trinitrate (GTN), but the activity of MGST1 towards GTN was 2-3 fold higher. To mimic oxidative/nitrosative stress in vitro, we treated enzyme preparations with hydrogen peroxide, S- nitrosoglutathione and peroxynitrite. Both oxidants and nitrating reagents increased the activity of MGST1 towards the GST substrate, 1-chloro-2,4-dinitrobenzene (CDNB) whereas these treatments inhibited GTN denitration by MGST1. Alkylation of the sole cysteine residue of MGST1 by N-ethylmaleimide markedly increased enzyme activity with CDNB as substrate but decreased the rate of GTN denitration. In aortic microsomes from GTN-tolerant animals, there was a decreased abundance of MGST1 dimers and trimers. In hepatic microsomes from GTN-tolerant animals, GTN biotransformation was unaltered whereas the rate of CDNB conjugation was doubled, suggesting that chronic GTN exposure causes structural modifications to the enzyme resulting in increased activity to certain substrates. Collectively, these data indicate that MGST1 contributes significantly to the biotransformation of GTN, and that chemical modification of the microsomal enzyme has differential effects on the catalytic activity towards different substrates.


Key words: biotransformation, glutathione S-transferase, glyceryl trinitrate, hepatic, microsome, vascular smooth muscle


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