AKR1C1

AKR1C1 Full Name

aldo-keto reductase family 1, member C1 (dihydrodiol dehydrogenase 1; 20-alpha (3-alpha)-hydroxysteroid dehydrogenase)

AKR1C1 Introduction

AKR1C1 is expressed in a wide range of human tissues, with the highest expression in tissues that are involved in steroid hormone metabolism or that are targets of hormone action. The liver contains abundant AKR1C1, where the enzyme contributes to the clearance and inactivation of circulating steroids and xenobiotics. The lung expresses high levels of AKR1C1, particularly in bronchial epithelial cells, where the enzyme may protect against inhaled aldehydes and pollutants. The prostate gland contains substantial AKR1C1, and the enzyme is thought to regulate the local concentration of androgens within the prostate. The breast and uterus also express AKR1C1, and the enzyme modulates the activity of estrogens and progestins in these tissues. Moderate expression is found in the kidney, adrenal gland, and placenta, while lower expression is detected in the brain, heart, and skeletal muscle. Within the cell, AKR1C1 is primarily cytosolic, consistent with its role in metabolizing cytosolic substrates. However, in hormone-responsive tissues, a fraction of AKR1C1 translocates to the nucleus, where it may interact with nuclear receptors or regulate the local concentration of steroid hormones that act through nuclear receptors. The protein lacks any known signal peptide, and its subcellular distribution is determined by its interactions with binding proteins and by its post-translational modifications.

Figure 1. Schematic structure of AKR1C1.

Enzymatic Properties and Substrate Specificity

AKR1C1 exhibits broad substrate specificity and can reduce a wide variety of carbonyl-containing compounds. The enzyme is particularly efficient at reducing ketosteroids, converting the potent androgen 5-alpha-dihydrotestosterone to its less active metabolite 3-alpha-diol, and converting the potent estrogen estrone to the less active estradiol. AKR1C1 also reduces the androgen precursor androstenedione to androsterone, and reduces the glucocorticoid cortisol to its inactive metabolite 20-dihydrocortisol. The enzyme has strong 20-alpha-hydroxysteroid dehydrogenase activity, converting progesterone to 20-alpha-hydroxyprogesterone, which is biologically inactive. In addition to steroids, AKR1C1 reduces prostaglandin D2 to 9-alpha,11-beta-prostaglandin F2, and reduces the prostaglandin precursor prostaglandin H2 to various metabolites. The enzyme also detoxifies reactive aldehydes generated during lipid peroxidation, including 4-hydroxynonenal and malondialdehyde. Finally, AKR1C1 reduces ketone-containing drugs, such as the anticancer agent doxorubicin and the non-steroidal anti-inflammatory drug ketoprofen. The catalytic mechanism follows an ordered sequential pathway in which NADPH binds first, followed by the carbonyl substrate.

AKR1C1 as a Therapeutic Target
AKR1C1 is a potential therapeutic target for hormone-dependent cancers, inflammatory diseases, and conditions involving oxidative stress. For prostate cancer, inhibitors of AKR1C1 could prevent the inactivation of 5-alpha-dihydrotestosterone, thereby reducing androgen receptor signaling and slowing tumor growth. However, this approach would need to be carefully balanced against the effects of AKR1C1 in other tissues, as systemic inhibition might alter steroid hormone levels throughout the body. For breast cancer, the role of AKR1C1 is more complex, as the enzyme both activates estrogens and inactivates progestins. Inhibiting AKR1C1 in breast cancer might have both beneficial and detrimental effects, depending on the hormone receptor profile of the tumor. For endometrial cancer, AKR1C1 inhibition might restore progesterone signaling and inhibit tumor growth. In addition to cancer, AKR1C1 inhibitors could be used to reduce the cardiotoxicity of doxorubicin by preventing the formation of the cardiotoxic metabolite doxorubicinol.

Alternate Names for AKR1C1

AKR1C1; aldo-keto reductase family 1, member C1 (dihydrodiol dehydrogenase 1; 20-alpha (3-alpha)-hydroxysteroid dehydrogenase); DDH1; aldo-keto reductase family 1 member C1; DD1; DDH; HAKRC; MBAB; aldo-keto reductase C