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  • Title: Mechanism-based partial inactivation of glutathione S-transferases by nitroglycerin: tyrosine nitration vs sulfhydryl oxidation.
    Author: Lee WI, Fung HL.
    Journal: Nitric Oxide; 2003 Mar; 8(2):103-10. PubMed ID: 12620373.
    Abstract:
    Liver glutathione-S-transferases (GSTs) are responsible for the detoxification of electrophiles, and specifically for the metabolism of orally administered organic nitrates such as nitroglycerin (NTG). Recent studies showed that reactive nitrogen species produced by tetranitromethane (TNM), peroxynitrite, or the myeloperoxidase/H2O2/nitrite system can inactivate GST. It is not known whether NTG can similarly inactivate liver GSTs, and if shown, by what mechanism(s). We incubated purified GSTs with NTG, S-nitroso-N-acetylpenicillamine (SNAP), TNM, or vehicle (5% dextrose, D5W), followed by determination of GST activity. Incubation of GST with NTG and TNM caused significant decreases in GST activity whereas no changes were observed with SNAP or D5W. The relative GST activity (vs preincubation) was 73+/-14% for NTG, 37+/-8% for TNM, 98+/-13% for SNAP, and 98+/-9% for D5W, respectively. Exogenous glutathione (GSH) prevented both NTG- and TNM-induced changes in GST activity, consistent with the observed oxidative modification of GST, such as -SH oxidation and dimerization of oxidized GST. In contrast, NTG and TNM exhibited substantial differences in their ability to nitrate tyrosine (TYR) sites in GST. These results demonstrated that NTG can reduce the activity of its own metabolizing enzyme such as GST and this inhibitory effect of NTG was unlikely to be mediated through NO, as such, since SNAP had no effect on GST activity. The partial inactivation of GST by NTG appeared to involve -SH oxidation, but not TYR nitration. These findings provided the first evidence of mechanism-based protein inactivation by NTG, and may lend insight into the hepatic metabolism of NTG and other organic nitrates after repeated oral exposure.
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