Commonwealth of Australia 2010
Metabolism/biotransformation
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- 31.4Elimination/Excretion
- 31.4.1Inhalation
- 31.4.3Dermal
31.3Metabolism/biotransformationAlthough cyanide can interact with substances such as methemoglobin in the bloodstream, the majority of cyanide metabolism occurs within the tissues (NTP, 1993). The metabolism of cyanide has been studied in animals and one major route and several minor routes found, as illustrated in Figure 8. (ATSDR, 2006). It is suggested that these metabolic routes are potentially common to many animals including wildlife species; however, information is not available for all animal species, and thus it cannot be excluded that alternative metabolic processes may potentially occur. The major metabolic pathway in animals is the conversion to thiocyanate by either rhodanese or 3-mercaptopyruvate sulphur transferase (*Wood and Cooley, 1956; Turner, 1969). In this metabolic pathway rhodanese catalyses the transfer of the sulfane sulphur of thiosulphate to the cyanide ion to form thiocyanate. Once thiocyanate is formed, it is not converted back to cyanide (ATSDR, 2006). Thiocyanate has been shown to account for 60% to 80% of an administered cyanide dose (*Blakley and Coop, 1949; *Wood and Cooley, 1956). The tissue distribution of rhodanese is highly variable in different animal species (*Himwich and Saunders, 1948). In dogs, the highest activity of rhodanese was found in the adrenal gland, approximately 2.5 times greater than the activity in the liver. Monkeys, rabbits, and rats had the highest rhodanese activity in the liver and kidney, with relative low levels in the adrenals, and higher total rhodanese activity than in dogs. Low levels of rhodanese activity were found in the brain, testes, lungs, spleen and muscle among various species. In addition to rhodanese a number of other sulphurtransferases can metabolise cyanide; and albumin, which carries elemental sulphur in the body in the sulfane form, may aid in the catalysis of cyanide to thiocyanate (*Westley et al., 1983). In brushtail possums, where cyanide is converted predominantly to thiocyanate, enzymatic activity (thiosulphate:cyanide sulphurtransferase) was ~50% lower in the liver of the possum than in dogs and may be higher in the kidney than liver (Turner, 1969).
A species difference was seen in the metabolism of cyanide to thiocyanate in rats, pigs and goats following a single oral dose of 3.0 mg KCN/kg bw by gavage (Sousa et al., 2002). Maximum thiocyanate levels were detected in the plasma 3, 6 and 6 hours post dosing in the goat (55.2 mol/L), rat (58.1 mol/L), and pig (42.8 mol/L) respectively. Over 24-hours post dosing, thiocyanate levels in rats were significantly higher than in pigs, and levels in goats were significantly higher than pigs at 3 and 18 hours. The biological half-life of thiocyanate in plasma was highest in the goat (13.9 hours). Minor metabolic pathways that have been investigated include: conversion of cyanide to 2-aminothiazoline-4-carboxylic acid (*Wood and Cooley, 1956; Turner, 1969); incorporation into a 1-carbon metabolic pool (*Boxer and Rickards, 1952), or combining with hydroxocobalamin to form cyanocobalamin (Vitamin B12) (*Ansell and Lewis, 1970). Conversion to 2-aminothiazoline-4-carboxylic acid excreted in urine accounted for about 15% of an administered cyanide dose in rats (*Wood and Cooley, 1956). However, this compound was not detected in the urine of brushtail possums administered a solution by stomach intubation equivalent to a dose of 3 mg NaCN/kg bw (Turner, 1969).
The minor pathway for metabolism of cyanide in mammalian systems in which cyanide chemically combines with the amino acid cysteine is shown in Figure 8. (*Ansell and Lewis, 1970). This chemical reaction yields cysteine and -thiocyanoalanine that is further converted to form 2-aminothiazoline-4-carboxylic acid and its tautomer, 2-iminothiazolidiene-4-carboxylic acid (ATSDR, 2006). Reactions of cyanide with the salts or esters of some amino acids (e.g. pyruvate, -ketoglutarate, oxaloacetate) led to the formation of cyanohydrin intermediates and their incorporation into intermediary metabolism (ATSDR, 2006). The ability of cyanide to form complexes with some metallic ions such as cobalt is the basis for the reaction with hydroxocobalamin that yields cyanocobalamin (Vitamin B12). Cyanocobalamin, which contains cyanide and cobalt, is essential for the health of mammalian organisms (ATSDR, 2006). 31.4Elimination/ExcretionAbsorbed cyanide is mainly excreted as thiocyanate in the urine following oral administration; however, traces of cyanide may also be excreted unchanged or as a variety of metabolic products (e.g. carbon dioxide, -thiocyanoalanine) in expired air, saliva, and sweat (*Friedberg and Schwarzkopf, 1969; Turner, 1969; *Hartung, 1982). 31.4.1InhalationNo animal studies are available investigating the elimination of cyanide following inhalation. 31.4.2OralWhen rats were given 2 mg CN/kg as [12C] KCN, urinary excretion of radioactivity reached 47% of the dose within 24 hours of administration (*Farooqui and Ahmed, 1982). When radiolabelled [14C] NaCN was injected subcutaneously into rats at a level of 8.3 µmol, no difference in radioactivity eliminated was observed between a group pre-treated for 6 weeks with a diet containing 0.7 mg CN/kg as KCN and matching controls (*Okoh, 1983). Most (89%) of the radioactivity was detected in the urine by 24 hours, and thiocyanate was the major metabolite. About 4% of the radioactivity was expired via the lungs, mostly as carbon dioxide. In brushtail possums administered a single dose of cyanide solution by stomach intubation equivalent to a dose of 3 mg NaCN/kg bw, urinary excretion of thiocyanate accounted for 62%-76% of the administered dose in the first 6 days, with most in the first 2 days (Turner, 1969). 31.4.3DermalNo studies are available investigating the elimination of cyanide following dermal exposure. Directory: data -> assets -> word doc -> 0017 0017 -> National Industrial Chemicals Notification and Assessment Scheme word doc -> Priority Existing Chemical word doc -> Rail safety news issue 6 – October 2011 word doc -> Review of Multiple Chemical Sensitivity: Identifying 0017 -> Rail Safety News Edition 8, December 2012 0017 -> Real-Time License Plate Localisation on fpga 0017 -> Careers network bulletin issue 6 July 16 2012 0017 -> Wiser science: Finding References inspec for Physics and Engineering 0017 -> Part A: Depth Study: The globalising world Popular culture and public policy Download 2.29 Mb. Share with your friends:
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