Citation:

KENNEKE, J. F., C. S. MAZUR, AND A. W. GARRISON. ENANTIOSELECTIVE FORMATION OF THE TRIAZOLE FUNGICIDE TRIADIMENOL FROM TRIADIMEFON IN MAMMAL AND FISH HEPATIC MICROSOMES. Presented at 234th National American Chemical Society Meeting, Boston, MA, August 19 - 23, 2007.

Impact/Purpose:

This task is divided into four major research areas: (1) Development of computational tools and databases for screening-level modeling of the environmental fate of organic chemicals; (2) Metabolism of xenobiotics: Enhancing the development of a metabolic simulator; (3) Metabonomics: The use of advanced analytical tools to identify toxicity pathways; and (4) Software infrastructure to support development and application of transformation/metabolic simulators.

For many chemicals, multiple transformation/metabolic pathways can exist. Consequently, transformation/metabolic simulators must utilize transformation rate data for prioritization of competing pathways. The prioritization process thus requires the integration of reliable rate data. When this data is absent, it is necessary to generate a database with metabolic and transformation rate constants based on: (1) experimentally measured values, including those requiring the use of advanced analytical techniques for measuring metabolic rate constants in vivo and in vitro; (2) rate constants derived from SPARC and mechanistic-based QSAR models; and (3) data mined from the literature and Program Office CBI. A long-term goal of this project is to build this database. This information will be used to enhance the predictive capabilities of the transformation/metabolic simulators. As indicated previously, exposure genomics, which provide early signs of chemical exposure based on changes in gene expression, will be used to guide chemical fate and metabolism studies. The incorporation of exposure genomics into fate studies will provide information concerning (1) the minimal concentrations at which biological events occur; and (2) the identification of biologically relevant chemicals(s) in mixtures.

The capability of categorizing chemicals and their metabolites based on toxicity pathway is imperative to the success of the CompTox Research Program. Metabonomics, which is the multi-parametric measurement of metabolites in living systems due to physiological stimuli and/or genetic modification, provides such a capability. The application of metabonomics to toxicity testing involves the elucidation of changes in metabolic patterns associated with chemical toxicity based on the measurement of component profiles in biofluids, and enables the generation of spectral profiles for a wide range of endogenous metabolites. Metabolic profiles can provide a measure of the real outcome of potential changes as the result of xenobiotic exposure.

Description:

Triazole containing compounds are used extensively in both agriculture and medicine for the control of fungal infections. Recently, emphasis has been placed on the potential adverse effects of these compounds within mammalian systems. Triadimefon is a common agricultural fungicide. It contains one chiral center, and forms a second chiral center when metabolized to triadimenol, another commercially used fungicide. We have studied the enantioselective metabolism of the individual enantiomers and racemate of triadimefon to triadimenol in microsomes from male and female mammals, fish and invertebrates. In all species and genders, (+) triadimefon was metabolized more quickly than (-) with the enantiomeric fractions of the resulting four triadimenol enantiomers being species specific. Inhibitor and pure enzyme studies indicated that triadimefon was metabolized by a short-chain dehydrogenase/reductase and may disrupt steroid pathways. These findings will be put in context of species differences, potential impacts on steroidogenesis and tumorigenesis, and risk assessment.

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