Chronic cyanide intoxication is a public health problem with drastic deleterious effects on a very large number of people in the agrarian tropics, where consumption of foods rich in cyanogenic glycosides in widespread. Similar but less drastic effects occur in modern industrial society, where frequent exposure to smaller amounts of cyanide from many sources is increasingly unavoidable. Systematic development of rational strategies for combatting these effects will depend on a correct detailed understanding of the natural mechanisms of cyanide detoxication. Such an understanding is presently lacking. The long term objectives of the proposed research are to relieve this deficiency and thereby to initiate a rational prophylactic approach to the practical problem. Since there is little doubt that cyanide is detoxified in mammals principally by conversion to thiocyanate in a reaction with some from of sulfane sulfur, the first specific aim of this research is to establish the quantitative sulfane sulfur distribution profiles of blood and various tissues. Because serum albumin has been shown to be capable of transporting sulfane sulfur, and additional aim is the characterization of the albumin binding sites for sulfur in relation to the sites previously established for a variety of other metabolites and drugs. Since serum albumin can also catalyze the detoxifying reaction of its sulfane sulfur with cyanide, a further aim is to establish the sources and circumstances of sulfur loading and unloading in normal metabolism. Finally, the beginnings of a prophylactic strategy will be sought in efforts to augment selectively the sulfane sulfur profiles of blood and tissues, and the relevance of such manipulation will be sought in radioisotopic tracer kinetic studies in vivo. The results of these studies are expected to be importance in the recognition, treatment, and prevention of disease conditions, often of complex etiology, involving chronic intoxication with cyanide.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM030971-06
Application #
3278876
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1984-04-01
Project End
1992-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Chicago
Department
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Nandi, D L; Horowitz, P M; Westley, J (2000) Rhodanese as a thioredoxin oxidase. Int J Biochem Cell Biol 32:465-73
Nandi, D L; Westley, J (1998) Reduced thioredoxin as a sulfur-acceptor substrate for rhodanese. Int J Biochem Cell Biol 30:973-7
Jarabak, R; Westley, J; Dungan, J M et al. (1993) A chaperone-mimetic effect of serum albumin on rhodanese. J Biochem Toxicol 8:41-8
Jarabak, R; Westley, J (1991) Localization of the sulfur-cyanolysis site of serum albumin to subdomain 3-AB. J Biochem Toxicol 6:65-70
Westley, A M; Westley, J (1991) Biological sulfane sulfur. Anal Biochem 195:63-7
Jarabak, R; Westley, J (1990) Competitive partial inhibitors of serum albumin-catalyzed sulfur cyanolysis. J Biochem Toxicol 5:1-8
Westley, A M; Westley, J (1989) Voltammetric determination of cyanide and thiocyanate in small biological samples. Anal Biochem 181:190-4
Jarabak, R; Westley, J (1989) The sulfur-cyanolysis sites of serum albumin: metabolite competition studies. J Biochem Toxicol 4:255-61
Westley, J; Jarabak, R (1989) Appendix to the sulfur-cyanolysis sites of serum albumin: metabolite competition studies. Tight-binding inhibitions that yield atypical Henderson plots. J Biochem Toxicol 4:263-5
Westley, J (1988) Mammalian cyanide detoxification with sulphane sulphur. Ciba Found Symp 140:201-18

Showing the most recent 10 out of 16 publications