Androstenedione, formation

Deuterium solvent IE in the androstenedione formation from progesterone... 

Wood, A.W., DC. Swinney, P.E. Thomas, D.E. Ryan, P.E Hall, W. Levin et al. (1988). Mechanism of androstenedione formation from testosterone and epitestosterone catalyzed by purified cytochrome P-450b. J. Biol. Chem. 263, 17322-17332. 

A number of inhibitors have been published [2035, 2037, 2211-2215], For reviews see [2216-2219], Abiraterone is a leading inhibitor, currently approved for use for prostate cancer [2220-2225], Another dmg in clinical trials is orteronel (TAK-700), which shows selective inhibition of the lyase reaction [2174, 2226], The concept is to block androgen production (i.e., androstenedione formation) and maintain production of other steroids for normal physiology. 

Tagashira, H., Kominami, S., and Takemori, S. (1995) Kinetic studies of cytochrome P-45017 alpha, lyase dependent androstenedione formation from progesterone. Biochemistry, 34 (34), 10939-10945. 

FIGURE 4.82 Mechanism for the formation of estrone from androstenedione by aromatase. 

An exactly analogous enzymic transformation is encountered during the formation of oestrogen and androgen sex hormones, e.g. estradiol and testosterone respectively, where dehydroepiandrosterone is oxidized to androstenedione. 

Testosterone metabolism. The lipido-ste-rol extract (LSESr, Permixon) was studied in primary cultures of epithelial cells and fibroblasts separated from benign prostate hypertrophy and prostate cancer tissues. The extract inhibited the formation of the T metabolites androstenedione 5 4 and 5 a-DHT The lipophilic extracts of fruits inhibited T 5p-reductase (EC 1.3.99.5) (5(xR). For fatty acid-like 5(xR inhibition a strongly polar end-group and a molecular skeleton allowing nonpolar interactions with the enzyme were required. The result indicated that 5pR activity in prostatic tissue may be influenced by the lipid environ-... 

The pL (L = H or D) dependence of the solvent DIEs associated with progesterone 493 oxidation to 17a-hydroxyprogesterone 494 and 17-0-acetyltestosterone 495 and 17a-hydroxyprogesterone oxidation to androstenedione 496 has been determined in microcosms from pig testes580 (equation 290). The initial rate of oxidation of 493 to 494 has been associated with the pL-independent inverse solvent isotope effect (SIE) (fce/ D = 0.75 — 0.95 in 30% DOD) while the oxidation of 495 has been associated with the pL-independent positive SIE in 30% DOD (ku/ku of about 2), DOD inhibited the formation of 496 from 444 in noncompetitive in pL-dependent manner. Androgens are synthesized from progesterone in a two-step reaction involving the 17a-hydroxylation... 

Figure 25 (a) The aromatase activity of P450 enzymes in which androstenedione is converted to estrone via oxidative deformylation (b) The concerted and radical mechanism of deformylation via breakdown of a peroxohemiacetal intermediate formed by nucleophilic attack of the ferric-hydroperoxo intermediate on the aldehyde (c) Abstraction of a alcohol hydrogen leads to the formation of a ketone rather than a ring... 

The resulting MO-TMS derivatives of numerous important compounds of this class are characterized by standard mass spectra and GC retention indices on standard nonpolar phases for their identification. The use of most active silylating reagents permits us to exclude the stage of O-methyl oxime formation, so far as ketosteroids can form the enol-TMS ethers. For example, androstenedione (II) gives the bis-O-TMS derivative ... 

Adrenal androgens also have a complex metabolic fate DHEA-S is formed in the adrenal cortex or by sulfokinases in the liver and kidney from DHEA and excreted by the kidney. DHEA and DHEA-S can be metabolized by 7a-and 16a-hydroxylases. 17p-Reduction of both compounds forms A -5-androstenediol and its sulfate. Androstenedione can be metabolized to androsterone after 3a- and 5a-reduction. 5P-Reduction results in the formation of etiocholanolone (see Eigure 51-7). These metabolites are conjugated to glucuronides and sulfates, which are then excreted in the urine. 

Circulating testosterone serves as a precursor for the formation of two types of active metabohtes (see Figure 53-3). Through the actions of 5a-reductase, 6%-8% of testosterone is converted to DHT. Alternatively, testosterone and androstenedione can be converted to estrogens ( 0.3%) through aromatase. DHT is formed in androgen target tissues, such as the skin and prostate, whereas aromatization... 

Aromatase inhibitors, e.g. anastrozole, letrozole and exemestane, restrict the formation of oestrogens from androstenedione and are new drugs used to treat breast cancer (Fig. 43.1). In fact, clinical trials of letrozole were so effective that the trials were stopped as it was considered unethical to continue with volunteers on placebo. 

CYP17A catalyzes both the 17a-hydroxylation of progesterone and subsequent cleavage of the C17-C20 bond to give androstenedione (Fig. 4.49). A similar transformation sequence accoimts for the conversion of pregnenolone to dehydroepiandrosterone. The favored mechanism for this reaction involves formation of the hydroperoxy hemiacetal with the ferric hydroper-oxy anion of the enzyme, followed by 0-0 bond homolysis, C-C bond homolysis, and finally recombination of the compormd II equivalent with... 

---