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Parman, T, et al., Toxicogenomics and Metabolomics of Pentamethylchromanol (Pmcol)-Induced Hepatotoxicity. Toxicol Sci, 2011. 124(2): 487-501.

SYNOPSIS

Metabolon results led to:
- Mechanism of compound derived hepatotoxicity
- A demonstration that metabolomics essentially serves as a noise reduction tool for toxicogenomics, prioritizing significant gene changes into a cohesive model

Key metabolomic observations:
- Depletion of total glutathione with compensatory effects on methionine and cysteine metabolism
- Depletion of the ophthalmate


Synopsis
Vitamin E has been widely investigated as a chemopreventative agent in several types of cancers. A vitamin E derivative (PMCol) has been shown to have antiandrogenic activity in prostate carcinoma cells but also hepatotoxicity, nephrotoxicity, and anemia in toxicity studies. Thus, investigators at SRI international used a toxicogenomic and metabolomic approach to understand the molecular basis of toxicological PMCol. The results revealed profound depletion of glutathione echoed by strong changes in pathways related to glutathione biosynthesis (cysteine and methionine metabolism and the trans-sulfuration pathway). A key clue to the source of the glutathione depletion came with the observation that a barometer for glutathione biosynthetic capacity, ophthalmate, was also depleted. This observation implicates PMCol in directly inhibiting glutathione biosynthesis. Importantly, by overlaying metabolomics onto gene expression data, a model for PMCol toxicology was produced that would not have been produced with gene expression data alone, suggesting that metabolomics would be an ideal companion for toxicology investigations.

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