title: Evidence for rapid inter- and intramolecular chlorine transfer reactions of histamine and carnosine chloramines: implications for the prevention of hypochlorous-acid-mediated damage.
abstract: Hypochlorous acid (HOCl) is a powerful oxidant generated from H(2)O(2) and Cl(-) by the heme enzyme myeloperoxidase, which is released from activated leukocytes. HOCl possesses potent antibacterial properties, but excessive production can lead to host tissue damage that is implicated in a wide range of human diseases (e.g., atherosclerosis). Histamine and carnosine have been proposed as protective agents against such damage. However, as recent studies have shown that histidine-containing compounds readily form imidazole chloramines that can rapidly chlorinate other targets, it was hypothesized that similar reactions may occur with histamine and carnosine, leading to propagation, rather than prevention, of HOCl-mediated damage. In this study, the reactions of HOCl with histamine, histidine, carnosine, and other compounds containing imidazole and free amine sites were examined. In all cases, rapid formation (k, 1.6 x 10(5) M(-)(1) s(-)(1)) of imidazole chloramines was observed, followed by chlorine transfer to yield more stable, primary chloramines (R-NHCl). The rates of most of these secondary reactions are dependent upon substrate concentrations, consistent with intermolecular mechanisms (k, 10(3)-10(4) M(-)(1) s(-)(1)). However, for carnosine, the imidazole chloramine transfer rates are independent of the concentration, indicative of intramolecular processes (k, 0.6 s(-)(1)). High-performance liquid chromatography studies show that in all cases the resultant R-NHCl species can slowly chlorinate N-alpha-acetyl-Tyr. Thus, the current data indicate that the chloramines formed on the imidazole and free amine groups of these compounds can oxidize other target molecules but with limited efficiency, suggesting that histamine and particularly carnosine may be able to limit HOCl-mediated oxidation in vivo.
authors.affiliation: The Heart Research Institute, 114 Pyrmont Bridge Road, Camperdown, Sydney, New South Wales 2050, Australia. pattisond@hri.org.au
authors.forename: David I
authors.initials: DI
authors.lastname: Pattison
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davies
mesh_terms: D001692:Biological Transport; D002331:Carnitine / Q000737:chemistry; D002700:Chloramines / Q000737:chemistry; D002713:Chlorine / Q000737:chemistry* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006632:Histamine / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006997:Hypochlorous Acid / Q000633:toxicity*; D007700:Kinetics; D013058:Mass Spectrometry; D016877:Oxidants / Q000633:toxicity; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D002700:Chloramines; D016877:Oxidants; D014443:Tyrosine; D006639:Histidine; D002713:Chlorine; D006997:Hypochlorous Acid; D006632:Histamine; C025787:N-acetyltyrosine; C030816:chloramine; D002331:Carnitine