title: The reaction of HOCl and cyanocobalamin: corrin destruction and the liberation of cyanogen chloride.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI 48201, USA; Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address: habusoud@med.wayne.edu.
authors.forename: Husam M
authors.initials: HM
authors.lastname: Abu-Soud
authors.affiliation: Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Dhiman
authors.initials: D
authors.lastname: Maitra
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jaeman
authors.initials: J
authors.lastname: Byun
authors.affiliation: Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Carlos Eduardo A
authors.initials: CEA
authors.lastname: Souza
authors.affiliation: Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Jashoman
authors.initials: J
authors.lastname: Banerjee
authors.affiliation: Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Ghassan M
authors.initials: GM
authors.lastname: Saed
authors.affiliation: Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Diamond
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, MI 48202, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Andreana
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: spennath@umich.edu.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
mesh_terms: D002851:Chromatography, High Pressure Liquid; D045728:Corrinoids / Q000737:chemistry* / Q000302:isolation & purification; D003486:Cyanides / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D006801:Humans; D006868:Hydrolysis; D006997:Hypochlorous Acid / Q000737:chemistry*; D007700:Kinetics; D010084:Oxidation-Reduction; D010949:Plasma / Q000737:chemistry; D013237:Stereoisomerism; D014805:Vitamin B 12 / Q000737:chemistry* / Q000302:isolation & purification
chemical_list: D045728:Corrinoids; D003486:Cyanides; C473700:corrin; C014430:cyanogen chloride; D006997:Hypochlorous Acid; D014805:Vitamin B 12