TY - JOUR
T1 - The reaction of HOCl and cyanocobalamin
T2 - Corrin destruction and the liberation of cyanogen chloride
AU - Abu-Soud, Husam M.
AU - Maitra, Dhiman
AU - Byun, Jaeman
AU - Souza, Carlos Eduardo A.
AU - Banerjee, Jashoman
AU - Saed, Ghassan M.
AU - Diamond, Michael P.
AU - Andreana, Peter R.
AU - Pennathur, Subramaniam
N1 - Funding Information:
This work was supported by National Institutes of Health Grants RO1 HL066367 and RO1 HL094230, the Children's Hospital of Michigan, the Doris Duke Foundation Clinical Scientist Development Award, and the Molecular Phenotyping Core of the Michigan Nutrition and Obesity Research Center (DK089503).
PY - 2012/2/1
Y1 - 2012/2/1
N2 - Overproduction of hypochlorous acid (HOCl) has been associated with the development of a variety of disorders such as inflammation, heart disease, pulmonary fibrosis, and cancer through its ability to modify various biomolecules. HOCl is a potent oxidant generated by the myeloperoxidase-hydrogen peroxide-chloride system. Recently, we have provided evidence to support the important link between higher levels of HOCl and heme destruction and free iron release from hemoglobin and RBCs. Our current findings extend this work and show the ability of HOCl to mediate the destruction of metal-ion derivatives of tetrapyrrole macrocyclic rings, such as cyanocobalamin (Cobl), a common pharmacological form of vitamin B12. Cyanocobalamin is a water-soluble vitamin that plays an essential role as an enzyme cofactor and antioxidant, modulating nucleic acid metabolism and gene regulation. It is widely used as a therapeutic agent and supplement, because of its efficacy and stability. In this report, we demonstrate that although Cobl can be an excellent antioxidant, exposure to high levels of HOCl can overcome the beneficial effects of Cobl and generate proinflammatory reaction products. Our rapid kinetic, HPLC, and mass spectrometric analyses showed that HOCl can mediate corrin ring destruction and liberate cyanogen chloride (CNCl) through a mechanism that initially involves α-axial ligand replacement in Cobl to form a chlorinated derivative, hydrolysis, and cleavage of the phosphonucleotide moiety. Additionally, it can liberate free Co, which can perpetuate metal-ion-induced oxidant stress. Taken together, these results are the first report of the generation of toxic molecular products through the interaction of Cobl with HOCl.
AB - Overproduction of hypochlorous acid (HOCl) has been associated with the development of a variety of disorders such as inflammation, heart disease, pulmonary fibrosis, and cancer through its ability to modify various biomolecules. HOCl is a potent oxidant generated by the myeloperoxidase-hydrogen peroxide-chloride system. Recently, we have provided evidence to support the important link between higher levels of HOCl and heme destruction and free iron release from hemoglobin and RBCs. Our current findings extend this work and show the ability of HOCl to mediate the destruction of metal-ion derivatives of tetrapyrrole macrocyclic rings, such as cyanocobalamin (Cobl), a common pharmacological form of vitamin B12. Cyanocobalamin is a water-soluble vitamin that plays an essential role as an enzyme cofactor and antioxidant, modulating nucleic acid metabolism and gene regulation. It is widely used as a therapeutic agent and supplement, because of its efficacy and stability. In this report, we demonstrate that although Cobl can be an excellent antioxidant, exposure to high levels of HOCl can overcome the beneficial effects of Cobl and generate proinflammatory reaction products. Our rapid kinetic, HPLC, and mass spectrometric analyses showed that HOCl can mediate corrin ring destruction and liberate cyanogen chloride (CNCl) through a mechanism that initially involves α-axial ligand replacement in Cobl to form a chlorinated derivative, hydrolysis, and cleavage of the phosphonucleotide moiety. Additionally, it can liberate free Co, which can perpetuate metal-ion-induced oxidant stress. Taken together, these results are the first report of the generation of toxic molecular products through the interaction of Cobl with HOCl.
KW - Aging
KW - Cobalt
KW - Corrin
KW - Cyanogen chloride
KW - Free metal toxicity
KW - Free radicals
KW - Inflammation
KW - Mammalian peroxidases
KW - Mass spectrometry
KW - Oxidative stress
KW - Porphyrin
KW - Stopped-flow
KW - Vitamin B12
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U2 - 10.1016/j.freeradbiomed.2011.10.496
DO - 10.1016/j.freeradbiomed.2011.10.496
M3 - Article
C2 - 22138102
AN - SCOPUS:84856280238
SN - 0891-5849
VL - 52
SP - 616
EP - 625
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 3
ER -