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  • br The role of cytochrome b with cytochrome P hydroxylase

    2023-09-15


    The role of cytochrome b5 with cytochrome P450 17α-hydroxylase/17,20-lyase
    Conclusion
    Acknowledgments LLM and RJR wish to thank the Australian Research Council and the National Health and Medical Research Council of Australia for funding.
    The problem One area of modern medicine that continues to evade us is the treatment of prostate cancer. Like breast cancer, prostate cancer is commonly referred to as an ‘endocrine’ cancer due to the fact initial growth is driven by naturally occurring C19 bioactive steroids, including testosterone and its respective metabolites [1]. Two recent approaches towards treatment of both of these steroid hormone-driven malignancies involve blockade of steroid binding to, or downregulation of androgen receptors (AR) [2] or estrogen receptors (ER) [3], respectively, or by inhibition of steroidogenic enzymes late in the steroidogenic pathway, particularly from the use of CYP19 (aromatase) inhibitors [4]. Steroid receptor blockade strategies, however, can fail due to treatment-induced removal of negative feedback regulation on hypothalamic gonadotropin releasing-hormone (GnRH) and pituitary gonadotropins, resulting in overdrive of endogenous steroid biosynthesis and so requiring accompanying GnRH analog therapy to ensure inhibition of pituitary gonadotropin release [5]. While steroid receptor antagonists may prove to be of future use, a more effective contemporary method is needed for controlling steroid biosynthesis in order to prevent induction of natural or drug-derived steroid ligands capable of driving tumor resurgence. An alternative approach to this problem would be to inhibit the biosynthesis of dehydroepiandrostenedione (DHEA), which in humans and nonhuman primates is an obligatory intermediate in all C19 steroid biosynthesis from CYP17A1 [6]. There has indeed been a great deal of excitement in the oncology field over recent success in going beyond the initial use of general steroid biosynthesis inhibitors, such as ketoconazole [7], and testing of newer CYP17A1 inhibitors, such as abiraterone [8], [9], [10] to limit DHEA biosynthesis. Recent trials have suggested that the CYP17A1 inhibition strategy is indeed successful, with ∼5months of additional overall survival accruing to subjects receiving abiraterone who had already developed castration resistant prostate cancer [11], [12], [13], [14], [15]. There is, nevertheless, a major problem that remains to be overcome; while tumor BD 1047 dihydrobromide sale develop steroid producing ability of their own, as in the case of prostate cancer [10], [13], [14], [15], they are not the major biosynthetic source of steroid hormones in the body. That title is clearly claimed by the adrenal, which dwarfs steroidogenic output by testes, ovaries or other organs, including adipose and the brain. There is also the specific problem that the CYP17 enzyme which creates DHEA and all subsequent C19 steroid metabolites, is also the same enzyme necessary for cortisol biosynthesis. Complete and absolute inhibition of CYP17 in itself creates major problems that we will detail below. Not only is it possible for normally circulating C19 steroids to drive these malignancies, but suppression of normal circulating levels of DHEA and androstenedione (A4) can also lead tumors themselves to locally express CYP17 and other enzymes necessary to maintain local biosynthesis [16]. In this review we will consider normal and alternate tumor biosynthesis of C19 steroids, and how the selective targeting in either case of 17,20 lyase activity inhibition, while sparing 17 hydroxylase activity, is the ‘holy grail’ necessary to overcome these problems.
    The search for a selective 17,20 lyase inhibitor—is it even possible? We now explore the evidence that selective lyase inhibition is indeed attainable. We then further explore how close the already established CYP inhibitors, and more recent compounds targeted to CYP17A1 in particular have progressed towards achieving that goal. Because the focus of this review is ultimately human therapy, we will focus only on the literature for species that show similar characteristics for CYP17A1 activity, namely humans and nonhuman primates, and we will also refer to data from the human-derived steroidogenic cell line, H295R, and its homologues. Before we begin, however, we first need to describe the normal role of CYP17A1 in steroid biosynthesis and ask what criteria can be effectively employed to distinguish between combined 17-hydroxylase and 17,20 lyase inhibition, and ‘true’, or ‘isolated’ 17,20 lyase deficiency. How much do circulating concentrations of steroids change in each instance? Can cortisol biosynthesis be preserved while completely inhibiting DHEA production? Fortunately the past 25 years have yielded an extensive understanding of the role of CYP17A1 in the normal adult male primate, and have allowed time to identify and characterize the outcomes of point mutations to the CYP17A1 gene itself, and indeed genes for accessory proteins (such as CytB5) that, when mutated selectively, impair 17,20 lyase activity while leaving 17 hydroxylase activity largely intact [31]. In many clinical trials, there is little reference to this basic steroidogenic literature, and yet it is key to both an understanding of the problem and achieving future therapeutic success. The data are indeed already there to guide the way to achieving our goal of a CYP17A1 selective drug capable of “clean” androgen ablation without ACTH excess.