Androgen biosynthesis

Singh SK, Pandey RS. 1990. Effect of sub-chronic endosulfan exposures on plasma gonadotrophins, testosterone, testicular testosterone and enzymes of androgen biosynthesis in rat. Indian J Exp Biol 28 953-956. 

The estrogens are a family of hormones synthesized in a variety of tissues. 17P-Estradiol is the primary estrogen of ovarian origin. In some species, estrone, synthesized in numerous tissues, is more abundant. In pregnancy, relatively more estriol is produced, and this comes from the placenta. The general pathway and the subcellular localization of the enzymes involved in the early steps of estradiol synthesis are the same as those involved in androgen biosynthesis. Features unique to the ovary are illustrated in Figure 42-7. 

Jarman M, Smith HJ, Nicholls PJ and Simons C (1998) Inhibitors of enzymes of androgen biosynthesis cytochrome P450 7l, and 5a-steroid reductase. Nat Prod Rep 15, 495-512. 

Fig. 10. Pathways of androgen biosynthesis in rat testis. A — B —> C and a —> b - c are the A5 and xlJ pathways, respectively, for testosterone biosynthesis. Enzymes A.a. 17-hydroxylase B.b, C-17,20-lyase C,c, 17j3-HSD. Reaction c is reversible.

In addition to weight determination and histology, there are several available methods for obtained additional information about the site of action and mechanism of a change in androgen biosynthesis. 

Androgen biosynthesis (secretory capacity for androgen precursors and testosterone) is assessed by incubation of the testis in vitro with hCG 250 mU for 3 hours. 

Klinefelter s syndrome (47, XXY) and mosaics Autosomal and sex chromosomes, polyploidies True hermaphroditism Defective androgen biosynthesis... 

Santen, R.J., H. Vanden Bossche, J. Symoens, J. Brugmans, and R. DeCoster (1983). Site of action of low dose ketoconazole or androgen biosynthesis in men. J. Clin. Endocrinol. Metab. 57, 732-736. 

Haidar, S., P.B. Ehmer, S. Barassin, C. Batzl-Hartmann, and R.W. Hartmann (2003). Effects of novel 17alpha-hydroxylase/C 17,20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J. Steroid Biochem. Mol. Biol. 84, 555-562. 

Control of androgen biosynthesis in the human through the interaction of Arg and Arg of CYP17 with cytochrome b. Biochem. J. 332, 293-296. 

The association between lifetime exposure to testosterone and DHT and the risk of developing prostate cancer suggests chemoprevention with specific inhibitors of key enzymes associated with androgen biosynthesis (127). Two key enzymes considered for inhibition are... 

A second enzyme system targeted for androgen inhibition is 17a-hydroxylase/17,20-lyase, which is the key enzyme that converts pregnenolone to DHAand, subsequently, to testosterone (Fig. 45.3). Because testosterone has androgenic activity, inhibition of its biosynthesis would be useful in treating androgen-dependent diseases, such as prostate cancer (130). Inhibitors of 17o-hydroxylase/17,20-lyase inhibitors could prevent androgen biosynthesis from both testes and adrenals and may provide effective treatment of patients with prostate cancer. 

Abiraterone acetate 117 is an androgen biosynthesis inhibitor, which was developed by the Institute of Cancer Research in the UK and further developed by Janssen for the oral treatment of patients with metastatic castration-resistant prostate cancer [75]. Its synthesis is relatively easy through a Suzuki coupling between the 17-enol triflate derived from the 3-acetate of dehydro-epiandrosterone (115) and 3-pyridyl-diethylborane (116) (Scheme 27) [76]. The reaction is catalysed by PdCl2(PPh3)2 and proceeds in good yield (84%). A similar Suzuki-based route in which the ketone starting material was converted into an alkenyliodide has also been published [77]. 

Rehman Y, Rosenberg JE (2012) Abiraterone acetate oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer. Drag Des Devel Ther 6 13-18... 

Tee MK, Dong Q, Miller WL (2008) Pathways leading to phosphorylation of p450cl7 and to the 2155. posttranslational regulation of androgen biosynthesis. Endocrinology 149 2667-2677... 

Biason-Lauber A, Leiberman E, Zachmann M (1997) A single amino acid substitution in the putative redox partner-binding site of P450cl7 as cause of isolated 17,20-lyase deficiency. J Clin Endocrinol Metab 82 3807-3812 Lee-Robichaud P, Akhtar ME, Akhtar M (1998) Control of androgen biosynthesis in the human through the interaction of Arg and Arg of CYP17 with cytochrome A5. Biochem J 332 293-296... 

Tee MK, Miller WL (2013) Phosphorylation of human cytochrome P450cl7 by p38a selectively increases 17,20 lyase activity and androgen biosynthesis. J Biol Chem 288 23903-23913... 

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