Cyanide is a highly toxic agent that inhibits mitochondrial cytochrome-c oxidase, thereby depleting cellular ATP. it contributes to smoke inhalation deaths in fires and could be used as a weapon of mass destruction. Cobalamin (vitamin B12) binds cyanide with a relatively high affinity and is used in Europe to treat smoke inhalation victims. Cobinamide, the penultimate compound in cobalamin biosynthesis, binds cyanide with about 1010 greater affinity than cobalamin, and we found It was several-fold more effective than cobalamin in (i) reversing cyanide inhibition of oxidative phosphorylation in mammalian cells; (ii) rescuing mammalian cells and Drosophila melanogaster from cyanide toxicity; and (iii) reducing cyanide inhibition of Drosophila Malpighian tubule secretion. Cobinamide could be delivered by oral ingestion, inhalation, or injection to Drosophila, and it was as effective when administered up to 5 mins post-cyanide exposure as when given preexposure. We conclude that cobinamide is an effective cyanide detoxifying agent that has potential use as a cyanide antidote, both in smoke inhalation victims and in persons exposed to cyanide used as a weapon of mass destruction.
SalkowskiAA, PenneyDG. Cyanide poisoning in animals and humans: a review. Vet Hum Toxicol36: 455–466, 1994.
2.
WayJL. Cyanide intoxication and its mechanism of antagonism. Annu Rev Pharmacol Toxicol24: 451–481. 1984.
3.
GreenfieldRA, BrownBR, HutchinsJB, landoloJJ, JacksonR, SlaterLN, BronzeMS. Microbiological, biological, and chemical weapons of warfare and terrorism. Am J Med Sci323: 326–340, 2002.
4.
RotenbergJS. Cyanide as a weapon of terror. Pediatr Ann32: 236–240, 2003.
5.
EcksteinM. Cyanide as a chemical terrorism weapon. JEMS29: 22–31, 2004.
6.
AlcortaR. Smoke inhalation & acute cyanide poisoning. Hydrogen cyanide poisoning proves increasingly common in smoke-inhalation victims. JEMS29: 6–15, 2004.
7.
AlarieY. Toxicity of fire smoke. Crit Rev Toxicol32: 259–289, 2002.
8.
EspositoFM, AlarieY. Inhalation toxicity of carbon monoxide and hydrogen cyanide gases released during the thermal decomposition of polymers. J Fire Sci6: 195–242, 1988.
SchefflerIE. Mitochondria make a come back. Adv Drug Delivery Rev49: 3–26, 2001.
11.
GraciaR, ShepherdG. Cyanide poisoning and its treatment. Pharmacotherapy24: 1358–1365, 2004.
12.
MooreSJ, NorrisJC, WalshDA, HumeAS. Antidotal use of methemoglobin forming cyanide antagonists in concurrent carbon monoxide/cyanide intoxication. J Pharmacol Exp Ther242: 70–73, 1987.
13.
HaywardGC, HillHAO, PrattJM, VanstonNJ, WilliamsARW. The chemistry of vitamin B(12). Part IV. 1. The thermodynamic trans-effect. J Chem Soc6485–6493, 1965.
14.
FortinJL, RuttimanM, DomanskiL, KowalskiJJ. Hydroxocobalamin: treatment for smoke inhalation-associated cyanide poisoning. Meeting the needs of fire victims. JEMS29: 18–21, 2004.
15.
SharmaVS, PilzRB, BossGB, MagdeD. Reactions of nitric oxide with vitamin B12 and its precursor, cobinamide. Biochemistry42: 8900–8908, 2003.
GuilbaultGG, KramerDN. Ultra sensitive, specific method for cyanide using p-nitrobenzaldehyde and o-dinitrobenzene. Anal Chem28: 834–836, 1966.
19.
SchefflerI. Carbohydrate Metabolism in Cultured Cells. New York: Plenum Press, pp 77–109, 1986.
20.
TickooS, RussellS. Drosophila melanogaster as a model system for drug discovery and pathway screening. Curr Opin Pharmacol2: 555–560, 2002.
21.
DemerecM. Biology of Drosophila. New York: John Wiley & Sons Inc, 1950.
22.
DowJT, DaviesSA. Integrative physiology and functional genomics of epithelial function in a genetic model organism. Physiol Rev83: 687–729, 2003.
23.
AgrawalN, PallosJ, SlepkoN, ApostolBL, BodaiL, ChangLW, ChiangAS, ThompsonLM, MarshJL. Identification of combinatorial drug regimens for treatment of Huntington's disease using Drosophila. Proc Natl Acad Sci U S A102: 3777–3781, 2005.
24.
ManevH, DimitrijevicN. Drosophila model for in vivo pharmacological analgesia research. Eur J Pharmacol491: 207–208, 2004.
van BuurenKJ, NicholisP, van GelderBF. Biochemical and biophysical studies on cytochrome aa 3. VI. Reaction of cyanide with oxidized and reduced enzyme. Biochim Biophys Acta256: 258–276, 1972.
30.
PandaM, RobinsonNC. Kinetics and mechanism for the binding of HCN to cytochrome-c oxidase. Biochemistry34: 10009–10018, 1995.
31.
Abou-SeifMA. Blood antioxidant status and urine sulfate and thiocyanate levels in smokers. J Biochem Toxicol11: 133–138, 1996.
32.
HasuikeY, NakanishiT, MoriguchiR, OtakiY, NanamiM, HamaY, NakaM, MiyagawaK, IzumiM, TakamitsuY. Accumulation of cyanide and thiocyanate in haemodialysis patients. Nephrol Dialysis Transplant19: 1474–1479, 2004.
33.
ZhangR, ShenZ, NauseefWM, HazenSL. Defects in leukocyte-mediated initiation of lipid peroxidation in plasma as studied in myeloperoxidase-deficient subjects: systematic identification of multiple endogenous diffusible substrates for myeloperoxidase in plasma. Blood99: 1802–1810, 2002.
34.
van DalenCJ, KettleAJ. Substrates and products of eosinophil peroxidase. Biochem J358: 233–239, 2001.
35.
ScanlonCE, BergerB, MalcomG, WisslerRW. Evidence for more extensive deposits of epitopes of oxidized low density lipoprotein in aortas of young people with elevated serum thiocyanate levels. PDAY Research Group. Atherosclerosis121: 23–33, 1996.
CartersonAJ, MoriciLA, JacksonDW, FriskA, LizewskiSE, JupiterR, SimpsonK, KunzDA, DavisSH, SchurrJR, HassettDJ, SchurrMJ. The transcriptional regulator AlgR controls cyanide production in Pseudomonas aeruginosa.J Bacteriol186: 6837–6844, 2004.
38.
KondoH, BinderMJ, KolhouseJF, SmytheWR, PodellER, AllenRH. Presence and formation of cobalamin analogues in multivitaminmineral pills. J Clin Invest70: 889–898, 1982.
39.
KanazawaS, TeradaH, IsekiT, IwasaS, OkudaK, KondoH, OkudaK. Binding of cobalamin analogs to intrinsic factor-cobalamin receptor and its prevention by R binder. Proc Soc Exp Biol Med183: 333–338, 1986.
40.
FedosovSN, BerglundL, FedosovaNU, NexoE, PetersenTE. Comparative analysis of cobalamin binding kinetics and ligand protection for intrinsic factor, transcobalamin, and haptocorrin. J Biol Chem277: 9989–9996, 2002.
41.
ErmensAA, VlasveldLT, LindemansJ. Significance of elevated cobalamin (vitamin B12) levels in blood. Clin Biochem36: 585–590, 2003.
42.
FedosovSN, PetersenTE, NexoE. Binding of cobalamin and cobinamide to transcobalamin from bovine milk. Biochemistry34: 16082–16087, 1995.
43.
KolhouseJF, KondoH, AllenNC, PodellE, AllenRH. Cobalamin analogues are present in human plasma and can mask cobalamin deficiency because current radioisotope dilution assays are not specific for true cobalamin. N Engl J Med299: 785–792, 1978.
44.
el KholtyS, GueantJL, BrasslerL, DjalaliM, BoisselP, GerardP, NicolasJP. Portal and biliary phases of enterohepatic circulation of corrinoids in humans. Gastroenterology101: 1399–1408, 1991.
45.
KondoH, KolhouseJF, AllenRH. Presence of cobalamin analogues in animal tissues. Proc Natl Acad Sci U S A77: 817–821, 1980.
46.
BakerH, FrankO, KhalilF, DeAngelisB, HutnerSH. Determination of metabolically active B12 and inactive B12 analog titers in human blood using several microbial reagents and a radiodilution assay. J Am Coll Nutr5: 467–475, 1986.
47.
KolhouseJF, AllenRH. Absorption, plasma transport, and cellular retention of cobalamin analogues in the rabbit. Evidence for the existence of multiple mechanisms that prevent the absorption and tissue dissemination of naturally occurring cobalamin analogues. J Clin Invest60: 1381–1392, 1977.
48.
KondoH, IsekiT, GotoS, OhtoM, OkudaK. Effects of cobalamin, cobalamin analogues and cobalamin binding proteins on P388D1 mouse leukemic cells in culture. Int J Hematol56: 167–177, 1992.
49.
WeinbergJB, ShugarsDC, ShermanPA, SaulsDL, FyfeJA. Cobalamin inhibition of HIV-1 integrase and integration of HIV-1 DNA into cellular DNA. Biochem Biophys Res Commun246: 393–397, 1998.
50.
CoatesME, DaviesMK, DawsonR, HarrisonGF, HoldsworthES, KonSK, PorterJW. The activity for chicks of some vitamin B12-like compounds. Biochem J64: 682–686, 1956.
51.
StablerSP, BrassEP, MarcellPD, AllenRH. Inhibition of cobalamin-dependent enzymes by cobalamin analogues in rats. J Clin Invest87: 1422–1430, 1991.
