Steroid hormones biosynthesis inhibition

Hormone Deprivation - Inhibition of Steroid Hormone Biosynthesis... 

The human body tunts over about 800 mg of cholesterol per day. Most of this turnover (synthesis, degradation, or loss from the body) inv olves bile salts. More specifically, about 400 mg cholesterol is used to manufacture new bile salts to replace those that have been lost in the feces. About 80 mg cholesterol is lost through the skin about 50 mg is used for synthesis of steroid hormones. Cholestyramine can stimulate the loss of much more than the equivalent of 400 mg, and can produce clinically significant decreases in serum cholesterol Cholestyramine alone does not drastically lower serum cholesterol, because the liver senses any depletion and responds by increasing its rate of cholesterol biosynthesis. However, use of the drug in combination with other drugs that Inhibit... 

Conclusive evidence that a species of cytochrome P-450 was involved in the hydroxylation was presented by Okuda et al., who showed that the photochemical action spectrum for reversal of the carbon monoxide inhibition of 26-hydroxylation of 5)8-cholestane-3a,7a,12a-triol in rat liver exhibited a maximum at 450 nm [134]. Pedersen et al. [135] and Sato et al. [136] reported simultaneously that small amounts of cytochrome P-450 could be solubilized from the inner membranes of rat liver mitochondria that was active towards cholesterol as well as 5)8-cholestane-3a,7a,12a-triol in the presence of ferredoxin, ferredoxin reductase and NADPH. The mechanism of hydroxylation is thus the same as that operative in the biosynthesis of steroid hormones in the adrenals and in the la-hydroxylation of 25-hydroxyvitamin D in the kidney (Fig. 8). The liver mitochondrial cytochrome P-450 was not active in the presence of microsomal NADPH-cytochrome P-450 reductase [135,136]. Ferredoxin reductase as well as ferredoxin were active regardless of whether they were isolated from rat liver mitochondria or bovine adrenal mitochondria [133]. The partially purified cytochrome P-450 had a carbon monoxide difference spectrum similar to that of microsomal cytochrome P-450 from liver microsomes and adrenal mitochondria. In the work by Pedersen et al. [133], the concentration of mitochondrial cytochrome P-450 in rat liver mitochondria from untreated rats was calculated to be only about 0.1 nmole/mg protein. Treatment of rats with phenobarbital increased the specific content of cytochrome P-450 in the mitochondria more than 2-fold, without significant increase in the 26-hydroxylase activity. The carbon monoxide spectrum of the reduced cytochrome P-450 solubilized from liver mitochondria of phenobarbital-treated rats exhibited a spectral shift of about 2 nm as compared to the corresponding spectrum obtained in analysis of preparations from untreated rats. This was taken as evidence that more than one species of cytochrome P-450 was present in the preparation. It was later shown by Pedersen et al. [137] and Bjbrkhem et al. [138] that the preparation was also able to catalyse 25-hydroxylation of vitamin D3 and that different enzymes are involved in... 

Yes, in high doses or with prolonged therapy. The decrease in cholesterol synthesis can affect the synthesis of steroid hormones. Additionally, the drug inhibits key enzymes in hormone biosynthesis, such as 14-a demethylase and 11-(3 hydroxylase, resulting in lower levels of androgens. 

Plant hormone biosynthesis and metabolism are influenced and modified, too, as already mentioned, by a large number of typical secondary plant constituents of quite different structures (Eef. 5, 6). For instance, it has been shown that some oi-disubstituted acetic acid derivatives are active both as antiauxins and as inhibitors of the biosynthesis of cyclic terpenoids. Thus, some more simple model compounds synthesized by ourselves, for example substituted a-phenoxy-isobutyrio acids, are not only competitive auxin inhibitors but they are also able to inhibit both the gibberellin and sterol biosynthesis. The same is true for some well known plant growth retardants, such as CCO or AMO 1618, which are inhibitors of gibberellin biosynthesis both in plants and in Fus ium moniliforme, but at the same time they are inhibiting and modifying also the biosynthesis of steroids in the respective organisms as well as in animal in vitro systems (Eef. 29) ... 

Most of the more recently described allenic steroids bear an allene group at the 17-position, which was usually formed by an SN2 substitution [106] or reduction [86d] process of a suitable propargylic electrophile. Thus, reduction of the pro-pargylic ether 109 with lithium aluminum hydride followed by deprotection of the silyl ether resulted in the formation of the allenic steroid 110, which irreversibly inhibits the biosynthesis of the insect moulting hormone ecdysone (Scheme 18.35) [107]. 

---