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In vitro studies of allelic variation and function of aldo-keto reductases 1A1 and 1C2 Takahashi, Ryan Hiro

Abstract

The aldo-keto reductases (AKR) are a superfamily of enzymes involved in metabolizing a variety of endogenous and xenobiotic chemicals. These biotransformation reactions are being recognized as important bioactivation or deactivation steps in humans that may determine the efficacy or toxicity of drug therapy or disease development. Consequently, the factors that affect the function of AKRs may be critical determinants for interpatient differences in therapeutic response and likelihood for disease occurrence. The metabolism of anthracycline drugs and androgen steroids are proposed to be involved in drug-induced cardiotoxicity and prostate cancer development, respectively. In the former case, the metabolism of anthracyclines can generate reactive species or toxic metabolites that are damaging to heart tissue. In the latter case, metabolic pathways that synthesize, interconvert, and deactivate androgen steroids regulate androgen receptor activation, and imbalance of these processes may promote abnormal prostate growth. The occurrence of both disorders is highly unpredictable, which may be, in part, due to interpatient variability in metabolism. The anthracyclines doxorubicin (DOX) and daunorubicin (DAUN) and the androgen steroid dihydrotestosterone (DHT) are substrates for two human isoforms of AKR protein, namely AKR1A1 and AKR1C2. Thus, factors affecting the function of these enzymes may contribute to altered metabolism and development of these conditions. The goal of this project is to characterize the function of AKR1A1 and AKR1C2 in metabolizing the anthracyclines DOX and DAUN, and the androgen steroid DHT using in vitro techniques. The naturally-occurring allelic variations in the coding regions of the AKR genes are compared to wild-type to identify their association with impaired reductase function. In addition, allosteric activation of AKR1C2, which has not been confirmed since its first report in the literature, is investigated for its relevance to DHT metabolism. The results of these studies demonstrate that genetic variation and chemical modulation can significantly alter the metabolism of DOX, DAUN, or DHT and, therefore, potentially contribute to the variability in patient response to these chemicals. These data can form a foundation of biochemical evidence to design in vivo studies that will elucidate the role of altered metabolism in developing anthracycline-associated cardiotoxicity and prostate cancer.

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