Aldo-Keto Reductases (AKRs) are a gene and protein superfamily whose members are expressed in all phyla. AKRs are principally, monomeric (37 kDa), cytosolic NAD(P)(H) oxidoreductases that catalyze the reduction of aldehydes and ketones to primary and secondary alcohols for conjugation reactions and thus can be called phase I enzymes. There are more than 173 members that fall into more than 15 families with broad substrate specificity ranging from sugar and lipid aldehydes, steroid hormones, prostaglandins, chemical carcinogens to carbonyl containing drugs (visit www.upenn.edu/akr). AKRs are also stress response genes, and because they arose early in evolution, they are often induced by primordial signals e.g. osmotic stress, electrophilic stress, oxidative stress and heat shock. There are 15 human AKRs and our focus has been on the structure-function of these enzymes and their roles in steroid hormone transformation and chemical carcinogenesis. Our studies show that the repertoire of reactions catalyzed by these enzymes can be extended to steroid double-bond reduction and nitroreduction. Human AKR1C enzymes are involved in the regulation of ligands for steroid hormone receptors, a process referred to as the pre-receptor regulation of steroid hormone action. In this context the role of AKR1C3 in the formation of potent androgens in castration resistant prostate cancer and its therapeutic targeting will be discussed. Human AKR1C enzymes are also involved in the metabolic activation of NO<sub>2</sub>-polycyclic aromatic hydrocarbons (PAH). In this context their role in the metabolic activation of 3-nitrobenzanthrone and their induction by Nrf2 will be described. In the context of NO<sub>2</sub>-PAH exposure Nrf2 activation may contribute to cancer initiation revealing a hitherto unrecognized dark-side to Nrf2 signaling.

Role of human aldo-keto reductases (AKRs) in hormonal & chemical carcinogenesis

2019 Fall National Meeting

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