The aims of this grant proposal are to investigate the toxicity and pharmacokinetics of chlordecone alcohol, the major human metabolite of chlordecone, a toxic organochlorine pesticide. The gerbil will serve as the primary test species because none of the other commonly used laboratory animals is capable of converting chlordecone to chlordecone alcohol. Because humans exposed to chlordecone retain chlordecone alcohol in their tissues, emphasis will be place on examining the time course and extent of chlordecone alcohol accumulation in gerbils treated with chlordecone or chlordecone alcohol. At the same time, efforts will be directed toward isolating, purifying, and characterizing chlordecone reductase from gerbil and human liver. This enzyme appears to be unique among """"""""aldo-keto reductases"""""""" in being absent from rats, rabbits, and guinea pigs, and in being inducible by its substrate, chlordecone. These results are expected to provide immediate impact on questions of long-term adverse health consequences to humans exposed to chlordecone in the environment. The results will also improve our understanding of the interaction of environmental agents with physiologic processes. Finally, the results will aid in establishing the human relevance of toxicologic studies in various species of experimental animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES001519-11
Application #
3249536
Study Section
Toxicology Study Section (TOX)
Project Start
1977-01-01
Project End
1988-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
11
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Mutter, L C; Blanke, R V; Jandacek, R J et al. (1988) Reduction in the body content of DDE in the Mongolian gerbil treated with sucrose polyester and caloric restriction. Toxicol Appl Pharmacol 92:428-35
Molowa, D T; Wrighton, S A; Guzelian, P S (1986) Purification and characterization of aldo-keto reductases from gerbil liver: immunochemical evidence for related proteins in other mammalian species. Arch Biochem Biophys 251:487-94
Molowa, D T; Shayne, A G; Guzelian, P S (1986) Purification and characterization of chlordecone reductase from human liver. J Biol Chem 261:12624-7
Molowa, D T; Wrighton, S A; Blanke, R V et al. (1986) Characterization of a unique aldo-keto reductase responsible for the reduction of chlordecone in the liver of the gerbil and man. J Toxicol Environ Health 17:375-84
Wrighton, S A; Maurel, P; Schuetz, E G et al. (1985) Identification of the cytochrome P-450 induced by macrolide antibiotics in rat liver as the glucocorticoid responsive cytochrome P-450p. Biochemistry 24:2171-8