Pyridoxamine Analogues Scavenge Lipid-Derived -Ketoaldehydes and Protect against H2O2-Mediated Cytotoxicity
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- 作者：Sean S. Davies ; Eric J. Brantley ; Paul A. Voziyan ; Venkataraman Amarnath ; Irene Zagol-Ikapitte ; Olivier Boutaud ; Billy G. Hudson ; John A. Oates ; L. Jackson Roberts II
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：December 26, 2006
- 年：2006
- 卷：45
- 期：51
- 页码：15756 - 15767
- 全文大小：274K
- 年卷期：v.45,no.51(December 26, 2006)
- ISSN：1520-4995
文摘
Isoketals and levuglandins are highly reactive 
-ketoaldehydes formed by oxygenation ofarachidonic acid in settings of oxidative injury and cyclooxygenase activation, respectively. Thesecompounds rapidly adduct to proteins via lysyl residues, which can alter protein structure/function. Weexamined whether pyridoxamine, which has been shown to scavenge 
-ketoaldehydes formed bycarbohydrate or lipid peroxidation, could also effectively protect proteins from the more reactive-ketoaldehydes. Pyridoxamine prevented adduction of ovalbumin and also prevented inhibition of RNaseA and glutathione reductase activity by the synthetic -ketoaldehyde, 15-E2-isoketal. We identified themajor products of the reaction of pyridoxamine with the 15-E2-isoketal, including a stable lactam adduct.Two lipophilic analogues of pyridoxamine, salicylamine and 5'-O-pentylpyridoxamine, also formed lactamadducts when reacted with 15-E2-isoketal. When we oxidized arachidonic acid in the presence ofpyridoxamine or its analogues, pyridoxamine-isoketal adducts were found in significantly greater abundancethan the pyridoxamine-N-acyl adducts formed by -ketoaldehyde scavenging. Therefore, pyridoxamineand its analogues appear to preferentially scavenge -ketoaldehydes. Both pyridoxamine and its lipophilicanalogues inhibited the formation of lysyl-levuglandin adducts in platelets activated ex vivo with arachidonicacid. The two lipophilic pyridoxamine analogues provided significant protection against H2O2-mediatedcytotoxicity in HepG2 cells. These results demonstrate the utility of pyridoxamine and lipophilicpyridoxamine analogues to assess the potential contributions of isoketals and levuglandins in oxidantinjury and inflammation and suggest their potential utility as pharmaceutical agents in these conditions.
-ketoaldehydes formed by oxygenation ofarachidonic acid in settings of oxidative injury and cyclooxygenase activation, respectively. Thesecompounds rapidly adduct to proteins via lysyl residues, which can alter protein structure/function. Weexamined whether pyridoxamine, which has been shown to scavenge -ketoaldehydes formed bycarbohydrate or lipid peroxidation, could also effectively protect proteins from the more reactive-ketoaldehydes. Pyridoxamine prevented adduction of ovalbumin and also prevented inhibition of RNaseA and glutathione reductase activity by the synthetic -ketoaldehyde, 15-E2-isoketal. We identified themajor products of the reaction of pyridoxamine with the 15-E2-isoketal, including a stable lactam adduct.Two lipophilic analogues of pyridoxamine, salicylamine and 5'-O-pentylpyridoxamine, also formed lactamadducts when reacted with 15-E2-isoketal. When we oxidized arachidonic acid in the presence ofpyridoxamine or its analogues, pyridoxamine-isoketal adducts were found in significantly greater abundancethan the pyridoxamine-N-acyl adducts formed by -ketoaldehyde scavenging. Therefore, pyridoxamineand its analogues appear to preferentially scavenge -ketoaldehydes. Both pyridoxamine and its lipophilicanalogues inhibited the formation of lysyl-levuglandin adducts in platelets activated ex vivo with arachidonicacid. The two lipophilic pyridoxamine analogues provided significant protection against H2O2-mediatedcytotoxicity in HepG2 cells. These results demonstrate the utility of pyridoxamine and lipophilicpyridoxamine analogues to assess the potential contributions of isoketals and levuglandins in oxidantinjury and inflammation and suggest their potential utility as pharmaceutical agents in these conditions.