Androstenedione biosynthesis

High-dose progestins are used as last-line endocrine therapy [223]. They inhibit the adrenal steroid biosynthesis. The decrease of estrogen levels is comparable to that caused by the administration of aromatase inhibitors. In post-menopausal women, the progestin megestrol acetate (MGA) decreases serum plasma level of DEAH, androstenedione and cortisol to less than 10% [223,224]. 

Fig. 2. Biosynthesis of testosterone (a) Pregnenolone (b) 17-hydroxy pregneno-line (c) dehydrois-oandrosterone (d) progesterone (e) 17-hydroxypro ges terone If androstenedione (g) testosterone...

Fig. 12. Classical pathways for oestrogen biosynthesis, indicating 19-hydroxylation and 19-oxidation of 4-androstenedione and testosterone, followed by C-10.19 bond cleavage catalysed by a presumed C-10.19-lyase.

The application of the twin ion technique [257] is also of importance in metabolism studies. The doubly labelled steroids [4- C+ 7-l- Ho.44]-androstenedione and [4- C + 7/3- Ho.42]-testosterone, were incubated with human placental microsomes and the resulting metabolites quantitated by counting C and identified by GC-MS [258]. The identified metabolites 17/8,19-dihydroxyandrost-4-en-3-one, 19-hydroxyandrost-4-en-3,17-dione, 17/8-hydroxy-3-oxo-androst-4-en-3-one, 3,17-dioxoandrost-4-en-19-al, oestradiol-17/3 and oestrone were easily recognisable from the double sets of relevant ions in their spectra due to the mixture of hydrogen and deuterium substitution at C-7. Hence the presence of the aromatizing enzymes in the placental preparation and the intermediates in oestrogen biosynthesis were confirmed. 

The accepted pathway for the biosynthesis of the oestrogens from the appropriate androgen substrate is shown in Scheme 2.1. The conversion of either testosterone (16) or androstenedione (17) to their respective oestrogens, oestradiol and oestrone, is catalysed by a E-450-NADPH-flavoprotein-reduc-tase-dependent enzyme complex, aromatase (AR) [143, 144]. The overall... 

The past decade has shown that hydrocarbon desaturation is not uncommon but, except in cases such as the biosynthesis of ergosterol, it generally accounts for a minor proportion of the metabolic products. The earliest reported example of P450-mediated hydrocarbon desaturation appears to be the conversion of lindane (1,2,3,4,5,6-hexachloro-cyclohexane) to 1,2,3,4,5,6-hexachlorocyclohex-ene, but the known hydrocarbon desaturation reactions now include the A -desaturation of androstenedione and deoxycorticosterone by adrenal mitochondria, the oxidation of dihydronaphthalene to naphthalene and 7,8-dihydrobenzo[a] pyrene to benzo[a]pyrene the conversion of warfarin to dehydrowarfarin ", the desaturation of lovostatin and simvastatin to the 6-exo-methylene... 

The direct desaturation of carbon adjacent to heteroatoms, notably oxygen and nitrogen, has also been observed. These reactions include the desaturation of a tetrahydrofuran ring in the biosynthesis of aflatoxin and sterigmatocystin by a specific P450 enzyme, the P450-catalyzed desaturation of flavanones to flavones, and the conversion of ethylcarbamate to vinyl carbamate . In some instances, the desaturation may involve the carbon and the heteroatom instead of two carbon atoms. The CYP2B1-catalyzed oxidation of testosterone to androstenedione, which involves oxidation of the 17-hydroxy to a 17-keto function, is possibly such a reaction, because only... 

Estrogens are biosynthesized in the maturing dominant foiiicle and in the corpus luteum in premenopausal women. During pregnancy, the placenta becomes the primary location of estrogen biosynthesis (5,6). Approximately 50% of estrone production occurs in the ovaries. The remaining estrone is biosynthesized from estradiol as well as from the conversion of estrone sulfate to estrone in the adrenal gland and the aromatization of androstenedione. In contrast to premenopausal women, in whom the natural estrone to estradiol ratio is 1 2, postmenopausal women have an estrone to estradiol ratio of 2 1, which reflects the loss of ovarian function. 

Androstenedione, mdrosl-4-ette-3,l7-dionc a weak androgen, and an intermediate in testosterone biosynthesis (see Androgens). 

CYP107A1 (P450 EiyF) Saccharopofyspora erythraea E.g., lOXA, 1Z80, lEGY, lEUP E.g., 6-deoxyerythronolide B, androstenedione, 9-aminophenan-threne, ketoconazole 6-Deoxyerythronolide B hydroxylase in erythromycin biosynthesis E.g., [34, 36, 773]... 

Biosynthesis without intermediate formation of androstenedione has been described using homogenates of human polycystic ovaries. Testosterone acetate is then assumed to be an intermediate. 

In the same studj these authors found a relatively substantial Cir-Cn desmolase activity in the placental compartment for 17a-hj droxyproges-terone, and they detected some Cw and Cis steroids (androstenedione, estrone, and estradioi-17/3), indicating that this precursor could be involved in the placental biosynthesis of androgens and estrogens. 

In the biosynthesis of estrone from J -androstenedione, or estradiol from testosterone, or estriol from 17a-hydroxytestosterone (Ryan, 1959), the aromatization of ring A is initiated by reactions designed to remove the angular C-19 methyl group (Meyer, 1955). It is now well-established that the first step is the hydroxylation of this carbon. The progression of reactions beyond this point is not yet clearly defined. However, from information available to date a pathway which appears most probable has been proposed (Fig. 16) (Longchampt et al., 1960b). 

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