Thiol-mediated catalysis of nitroglycerin degradation by serum proteins. Increase in metabolism was not accompanied by S-nitrosothiol production.

In vitro degradation of nitroglycerin (NTG) in human plasma has been shown to be accelerated significantly by sulfhydryl compounds. The interaction between NTG and N-acetyl-1-cysteine (NAC) in human plasma produces a pharmacologically active S-nitrosothiol, which may be responsible, at least in part, for the in vivo nitrate tolerance-reversing effect of NAC. The mechanism of this thiol-mediated NTG degradation in plasma has not been identified. In this report, we examined the catalytic activity of various plasma proteins toward NAC-mediated NTG degradation and found human serum albumin (HSA) to have the highest catalytic activity among the proteins tested. However, the dinitrate metabolite distribution ratio found with HSA (favoring the 1,3- over the 1,2-isomer) was substantially different from that observed with human plasma (where equal amounts of both dinitrates were produced). In addition, the HSA-catalyzed degradation of NTG did not lead to enhanced formation of S-nitrosothiol. These findings therefore argue against a predominant role exerted by HSA in the thiol-mediated NTG metabolism in plasma. The HSA-mediated catalysis of NTG was partially blocked by pretreatment with NAC followed by a thiol-alkylating agent, suggesting that the catalytic mechanism was due, in part, to the conversion of disulfide linkages within the HSA structure to reactive sulfhydryl groups.