Indole-3-carbinol (I-3-C), and other indole compounds protect against hepatotoxicity resulting from exposure to carbon tetrachloride (CCl4) or N-nitrosodimethylamine (NDMA). These indole compounds or their metabolities have the ability to scavenge radicals or electrophiles in vitro test systems. We propose to examine the following hypothesis: """"""""I-3-C, related indole derivatives, and/or their metabolites may act as (or generate) intracellular nucleophiles and/or radical scavengers. As such, these compounds may intervene in the toxicity resulting from exposure to chemicals which exert their effects via reactive electrophiles or free radicals"""""""". We will address this hypothesis with the following specific aims and general methods: (1) Determine the radical scavenging and electrophile trapping capabilities (nucleophilicity) of a series of indole and indolylindene derivatives. Radical scavenging is determined as an inhibition of phospholipid peroxidation; nucleophilicity is determined by competing a putative nucleophile with cysteine for methylation by limiting amounts of N-methyl-N- nitrosourea (MNU). (2) Determine the involvement of ascorbate in the mechanism of I-3-C protection from NDMA hepatotoxicity. Parameters of NDMA hepatotoxicity will include changes in sulfhydryl homeostasis, enzymatic parameters involved in electrophile and radical stress, parameters of mixed-function oxidase activity, liver histology, and release of liver enzymes into the serum. Since I-3-C protects against the depletion of ascorbate by NDMA, and ascorbate is highly reactive in scavenging carbonium cations, we will measure ascorbate concentrations and turnover in the course of NDMA toxicity in the absence and presence of indole compounds. (3) Continue to separate, identify and define the radical and electrophile trapping abilities of the metabolites of I-3-C. We are using HPLC separation techniques with UV detection, liquid scintillation counting and mass spectrometry. We are currently using (14C- carbinol)-I-3-C, but proposed to utilize (14C-benzene ring)-I-3-C. These studies will provide the basis for developing dietary and pharmacological strategies to reduce the risk associated with exposure to toxins that act via electrophilic or radical mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003373-05
Application #
3250623
Study Section
Toxicology Study Section (TOX)
Project Start
1984-05-01
Project End
1990-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Liu, R M; Nebert, D W; Shertzer, H G (1993) Menadione toxicity in two mouse liver established cell lines having striking genetic differences in quinone reductase activity and glutathione concentrations. Toxicol Appl Pharmacol 122:101-7
Liu, R M; Sainsbury, M; Tabor, M W et al. (1993) Mechanisms of protection from menadione toxicity by 5,10-dihydroindeno[1,2,-b]indole in a sensitive and resistant mouse hepatocyte line. Biochem Pharmacol 46:1491-9
Liang, H C; Shertzer, H G; Nebert, D W (1992) ""Oxidative stress"" response in liver of an untreated newborn mouse having a 1.2-centimorgan deletion on chromosome 7. Biochem Biophys Res Commun 182:1160-5
Shertzer, H G; Lastbom, L; Sainsbury, M et al. (1992) Menadione-mediated membrane fluidity alterations and oxidative damage in rat hepatocytes. Biochem Pharmacol 43:2135-41
Shertzer, H G; Bannenberg, G L; Moldeus, P (1992) Evaluation of iron binding and peroxide-mediated toxicity in rat hepatocytes. Biochem Pharmacol 44:1367-73
Shertzer, H G; Sainsbury, M; Graupner, P R et al. (1991) Mechanisms of chemical mediated cytotoxicity and chemoprotection in isolated rat hepatocytes. Chem Biol Interact 78:123-41
Tabor, M W; Coats, E; Sainsbury, M et al. (1991) Antioxidation potential of indole compounds--structure activity studies. Adv Exp Med Biol 283:833-6
Shertzer, H G; Sainsbury, M (1991) Chemoprotective and hepatic enzyme induction properties of indole and indenoindole antioxidants in rats. Food Chem Toxicol 29:391-400
Shertzer, H G; Bannenberg, G L; Rundgren, M et al. (1991) Relationship of membrane fluidity, chemoprotection, and the intrinsic toxicity of butylated hydroxytoluene. Biochem Pharmacol 42:1587-93
Shertzer, H G; Sainsbury, M (1991) Intrinsic acute toxicity and hepatic enzyme inducing properties of the chemoprotectants indole-3-carbinol and 5,10-dihydroindeno[1,2-b]indole in mice. Food Chem Toxicol 29:237-42

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