Testosterone metabolism, site

Kenworthy et al. [45] proposed a model with three subsites in order to explain the binding of testosterone (TS) and diazepam (DZ). One site binds diazepam, another binds testosterone, and the third is capable of binding either diazepam or testosterone. They found that testosterone caused extensive activation of diazepam metabolism, whereas diazepam caused inhibition of testosterone metabolism. Diazepam is present in the inhibitor database used to obtain the pharmacophoric model and its inhibitory activity is well explained by the model (y-residual = 0.27 log units). The model with multiple binding sites proposed by Kenworthy helped to explain the results of the obtained pharmacophoric model if one considers that competition will occur in the catalytic site that can bind either DZ or TS and that... 

Saw palmetto relieves urinary symptoms and flow measures associated with an enlarged prostate it does not reduce the enlargement. Saw palmetto is chiefly employed to manage prostatic enlargement or benign prostatic hyperplasia (BPH). A hexane extract inhibits 5-alpha reductase, the enzyme needed for the conversion of testosterone into dihydrotestosterone (DHT). Saw palmetto further antagonizes DHT binding at prostatic receptor sites, which increases the metabolism and excretion of DHT. It is also used to treat BPH-related inflammation (see Chapter 55). 

The liver synthesizes two enzymes involved in intra-plasmic lipid metabolism hepatic triglyceride lipase (HTL) and lecithin-cholesterol-acyltransferase (LCAT). The liver is further involved in the modification of circulatory lipoproteins as the site of synthesis for cholesterol-ester transfer protein (CETP). Free fatty acids are in general potentially toxic to the liver cell. Therefore they are immobilized by being bound to the intrinsic hepatic fatty acid-binding protein (hFABP) in the cytosol. The activity of this protein is stimulated by oestrogens and inhibited by testosterone. Peripheral lipoprotein lipase (LPL), which is required for the regulation of lipid metabolism, is synthesized in the endothelial cells (mainly in the fatty tissue and musculature). 

Meikle, A.W. Arver, S. Dobs, AS. Sanders, S.W. Rajaram, L. Mazer, N.A. Pharmacokinetics and metabolism of a permeation enhanced testosterone transdermal system in hypogonadal men influence of application site—clinical research center study. J. Clin. Endocrinol. Metab. 1996, 81, 1832-1840. 

Yu, Z. Gupta, S.K. Hwang, S.S. Cook, D.M. Duckett, M.J. Atkinson, L.E. Transdermal testosterone administration in hypogonadal men comparison of pharmacokinetics at different sites of application and at the first and fifth days of application. J. Clin. Pharmacol. 1997, 57, 1129-1138. Zobrist, R.H. Quan, D. Thomas, H.M. Stanworth, S. Sanders, S.W. Pharmacokinetics and metabolism of transdermal oxybutynin in vitro and in vivo performance of novel delivery system. Pharm. Res. 2003, 20, 103-109. Marzulli, E.N. Barriers to skin penetration. J. Invest. Dermatol. 1962, 39, 387-389. 

Ala245Ser and AIa245Thr mutant enzymes, it appears as though the loss of catalytic activity in the mutant forms correlates with the loss or repositioning of Wat519 (ref [234]). Nonetheless, these mutants are still able to metabolize the substrate testosterone at different sites, implying that a very intricate hydrogenbonding interplay exists between substrate and enz)mie. 

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