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.

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National Institute of Environmental Health Sciences (NIEHS)
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Toxicology Subcommittee 2 (TOX)
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University of Cincinnati
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