Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Sheryl S. Smith in Neurosteroid Effects in the Central Nervous System, 2003
In general, GABAA receptor inhibition seems to have fewer structural requirements than GABAA receptor potentiation. As mentioned previously, an anionic group (usually a sulfate group) at C3 seems important, though not necessary, as reviewed below. GABA-inhibiting steroids are approximately equally active with the charged moiety in the 3a or 3p configuration. Different steroid classes consisting of a pregnene, 5P- or 5α -reduced pregnane, or 5P- or 5α -reduced androstane can all support inhibition.12,13,81,82 Enantiomeric pairs for DHEAS, PS, and 3α 5p PS have been synthesized. In hippocampal neurons little enantioselectivity was found for PS and 3α 5p PS, although significant enantioselectivity (~8-fold) was found
The Role of Steroid Sulfatase and Sulfotransferase Enzymes in the Metabolism of C21 and Cl9 Steroids
Ronald Hobkirk in Steroid Biochemistry, 1979
The C19 and C21 steroids that were the most potent inhibitors for the steroid sulfatase in rat and human testes have been identified as metabolic products in studies with testicular preparation from these sources. Payne and Jaffe66 reported the isolation of in incubations of androstenediol-5α-androstane-3β,17β-diol and 5α-androstane-3α,17β-diol in incubations of androstenediol-3-sulfate, with a microsomal preparation from rat testes. They observed that 5α-androstane-3β,17β-diol, which had been shown to be the most potent C19 steroid inhibitor of the sulfatase activity,50 was the most abundant free steroid identified other than testosterone and androstenedione. In studies with isolated seminiferous tubules and minced tissue from human testes, Kawano et al.50 isolated 5-pregnene-3β,20α-diol in incubations with pregnenolone sulfate as the substrate. They demonstrated that steroid sulfatase and 20α reductase, the enzyme that converts pregnenolone to 5-preg-nene-3β,20α-diol, are localized predominantly in seminiferous tubules of the human testes. Payne and co-workers49,67 and Rivarola68 reported that the major concentration of 5α reductase, the enzyme essential for the production of 5α-androstane-3α,17β-diol, is also found predominantly in seminiferous tubules of human testes.
Androgen Metabolism in the Human Female
A. S. Curry, J. V. Hewitt in Biochemistry of Women: Clinical Concepts, 1974
The naturally occurring androgens share, with modifications, the molecular structure of the C19 steroid compound androstane. The steroid nucleus has a rigid planar structure and by convention substituents which lie below or above the plane of the molecule are designated a and β, respectively, where stereoisomerism is possible. The modifications in the androstane molecule, that are encountered in various characteristic combinations in androgens, include a carboxyl (C = 0) or hydroxyl (-OH) group at C-3, C-11, and C-17, a double bond either between C-4 and C-5 or C-5 and C-6. Figure 1 shows the structure of various C19 steroids which are relevant to this discussion.
Expression of cytochrome P450 isozyme transcripts and activities in human livers
Published in Xenobiotica, 2021
Jie Liu, Yuan-Fu Lu, J. Christopher Corton, Curtis D. Klaassen
Sex/gender differences in CYP enzymes are a common phenomenon in rodents (Waxman and Holloway 2009). Our Lab recently analysed 78 mouse CYP genes, and sex-dependent expression was observed with 27 CYPs, and 22 CYPs were higher in females including Cyp2a4, Cyp2b9, Cyp2c37, Cyp3a41, and Cyp4a14 (Renaud et al.2011). Human CYP3A4/5 is the most important P450 in human liver because it metabolises the most drugs, and is considered to be female-predominant (Waxman and Holloway 2009). CYP 3A activity can be assessed by midazolam disposition; women exhibited 16% higher weight-corrected midazolam oral clearance than men (Hu and Zhao 2010). In this study, the enzyme activity and mRNA of CYP3A4 as well as CYP2E1 tended to be higher in females. There is also evidence for females having higher activity of CYP2A6 and CYP2B6, but no differences in CPY2C9 and CYP2D6 activity (Anderson 2008). In this study, no major difference in CYP1A2, 2B6, 2C9, 2C19, 2D6, and 4A11 was evident. Sexually dimorphic regulation and induction of P450s could be mediated in part by the constitutive androstane receptor (CAR) (Hernandez et al.2009). Apparently, the dramatic sex-differences in CYP mRNA and enzyme activities seen in experimental animals (Renaud et al.2011) are not observed in humans.
Finasteride and androgenic alopecia; from therapeutic options to medical implications
Published in Journal of Dermatological Treatment, 2020
Ion G. Motofei, David L. Rowland, Mircea Tampa, Maria-Isabela Sarbu, Madalina-Irina Mitran, Cristina-Iulia Mitran, Anca Pantea Stoian, Camelia C. Diaconu, Stana Paunica, Simona R. Georgescu
After finasteride therapy, a number of cerebral neurosteroids remain disturbed, a condition that could explain the persistence of several symptoms after treatment cessation (sexual side effects, depression, anxiety, and cognitive complaints). Thus, decreased levels of progesterone and its corresponding metabolites (dihydroprogesterone and tetrahydroprogesterone), and increased levels of its precursor pregnenolone, have been detected in the cerebrospinal fluid of post-finasteride patients. In addition, a significant decreased level of dihydrotestosterone was registered, associated with increased levels of testosterone as well as of 3α-diol, 3β-diol, and 17β-estradiol. In plasma, studies have found a decreased level of dihydroprogesterone and increased levels for 5α-androstane-3α, 17β-diol, and 17β-estradiol (57–59).
Predominant contributions of carboxylesterase 1 and 2 in hydrolysis of anordrin in humans
Published in Xenobiotica, 2018
Jinfang Jiang, Xiaoyan Chen, Dafang Zhong
Anordrin (2α, 17α-diethynyl-A-nor-5α-androstane-2β, 17β-diol diproprionate) is domestically synthetic, steroid-like estrogen that is used in China as a post-coital contraceptive for more than 30 years (Chih-Ping et al., 1976; Gu et al., 1984). Anordrin is also marketed in combination with mifepristone (Sang et al., 1999). Anordrin is a selective estrogen receptor modulator, with both weak estrogenic and antiestrogenic properties (Mehta et al., 1981,1982; Chatterton et al., 1989). In cynomolgus monkeys, rapid hydrolysis of dipropionate esters is the main metabolic pathway, resulting in forming of unesterified anordriol (Chatterton et al., 1994) (Figure 1). Anordriol shows 36-fold higher affinity than anordrin for cytosol estrogen receptor of rat uterus in vitro, and is the main component responsible for resistance to pregnancy (Gu et al., 1984), thus anordrin can be called as a prodrug for the contraceptive indication. Moreover, α-anordrin shows inhibitory effect on multiple kinds of tumors (Bin et al., 1989; Ma et al., 2000), indicating that anordrin can be developed for variety of potential applications.
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