This study will examine in rodents and man the metabolism and potential toxicity of the proestrogenic pesticide methoxychlor and of one of its contaminants chlorotrianisene (TACE). Methoxychlor, used as a substitute for DDT, contains numerous contaminants some of which are proestrogenic and/or proantiestrogenic (e.g., TACE). Tamoxifen, a TACE analog, used as anti-breast cancer agent, will serve as a model triphenylethylene. The importance of studying these compounds is: a) they represent structural analogs of several classes of pesticidal and non-pesticidal xenobiotic compounds and b) they are environmental estrogens and toxic to sexual development and reproduction. The compounds are metabolized by several routes, yielding estrogens and antiestrogens by one route and reactive intermediates (RIs) by another route. The RIs bind to neighboring proteins and some RIs also bind to proteins at distant sites. The various RIs are formed by different P450 enzymes. There are also differences in RIs stability and direction of migration. Our observation that methoxychlor binds covalently to thyroxine deiodinase, the key enzyme forming the active thyroid hormone (T3), stimulates novel tracks of investigation. We'll determine: (i) the trafficking pattern of the RIs, (ii) the reason(s) for specificity of acceptor protein for RI, (iii) whether binding of the RIs is toxic, i.e., does methoxychlor inhibit T3 synthesis and elicits hypothyroid effect, and (iv) how different P450s (in consort and alone) orchestrate the divergent routes of metabolism and how is the balance maintained. To diminish the use of animals, we'll develop a breast cancer cell line to merge metabolism capability with estrogen detection. This should facilitate the determination of whether a xenobiotic is an estrogen, antiestrogen, proestrogen, proantiestrogen or is inactive. We'll investigate the mechanism for the high level of P4501A activity in immature rats; this enzyme catalyzes the covalent binding of TACE and converts procarcinogens into carcinogens. High levels of this enzyme in adult animal might be detrimental, however during development, the enzyme may be essential for disposing certain native compounds. We'll determine the mechanism of methoxychlor and TACE mediated inhibition of liver steroidal 5 alpha-reductase, an enzyme catalyzing the formation of dihydrotestosterone (DHT), an active male hormone, and whether diminished enzyme activity also occurs in the prostate. DHT causes prostatic hypertrophy, and lowering of its formation may actually be beneficial.
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