Testosterone, 6 3-hydroxytestosterone

A second example can be found in the metabolism of the male sex steroid hormone testosterone. In addition to 7a -hydroxy- and 6a-hydroxytestosterone, CYP2A1 was also found to form A6-testosterone (136) (Fig. 4.69). Using selectively deuterated analogs (136), A6-testosterone was established as being formed in competition with 6o -hydroxytestosterone after initial hydrogen atom abstraction from C6 to form the common radical intermediate. Little, if any, A6-testosterone was found to be formed in competition with la-hydroxytestosterone after initial hydrogen abstraction from Cl. 

Testosterone, lljS-hydroxytestosterone, and a polyene alcohol, probably far-nesol, were found in the urine of male yellowfin Baikal sculpin (C. grewingkt). Synthesized in the testes, these compounds are excreted with milt (Katsel etal., 1992). 

Testosterone enol diacetate reacts with perchloryl fluoride in aqueous dioxane to give 6a- and 6/i-fluorotestostcrone 17-acetatc (18 X = a-F, /i-F) as the major products along with 6a- and 6/3-hydroxytestosterone 17-acetate (18 X = a-OH, /j-OH) and also 17/i-hydroxyandrostane-3,6-dione 17-acctate.31 The enamine derivative 3-(pyrrolidin-l-yl)estra-3,5-dien-17/i-ol can be fluorinated in methanol at —25 to — 35 C to provide 4/J-fluoro-3a-methoxycstr-5-ene-3/f 17/ -diol (19),32 while various 2-fluoro-3-oxoestranc derivatives 20 are formed by fluorination of a number of 3-methoxyestrane derivatives in tetrahydrofuran/water mixture with perchloryl fluoride.33... 

A green cell suspension culture of Marchantia polymorpha, a liverwort, was shown to convert testosterone (Fig. 6.4) to 6(3-hydroxytestosterone and epitestosterone to androst-4-ene-3,17-dione (Hamada et at, 1991). The same culture was able to reduce the C-17 carbonyl of androst-4-ene-3,17-dione. It... 

Figure 2 Effect of age on the 6ft-, la-, and 16a-hydroxylation of testosterone by rat liver microsomes. Liver microsomes equivalent to 333 mg of wet-weight liver from male rats were incubated with 700 m/xmoles of testosterone-4-C14 in a final volume of 5.7 ml for 7.5 min at 37°C in the presence of an NADPH-generating system. Formation of 6ft-hydroxytestosterone (6/f-OH), 7a-hydroxytestosterone (7a-OH), and 16a-hydroxytestosterone (16a-OH) was measured. Each value represents the average SE of three to six values where each value was obtained with the pooled livers from three to six rats. Taken from Ref. (36).

Figure 10.15. Aromatization reactions catalyzed by P450 19. The three distinct steps are shown, with the possible substrates Testosterone, Rj -OH, Rj H androstenedione, Rj.- =0, R -OH 16-hydroxytestosterone,...

Smith, S.J., K.R. Korzekwa, T. Aoyama, F.J. Gonzalez, J.F. Darbyshire, K. Sugiyama et al. (1992). 12 alpha-hydroxytestosterone. A hitherto unidentified testosterone metabolite produced by cytochrome P-450 2A2. Drug Metab. Dispos. 20, 566-571. 

An enzyme-immunoassay for testosterone in female plasma and saliva uses lla-hydroxytestosterone 11-hydrogen succinate-horseradish peroxidase conjugate as enzyme label, and p-hydroxyphenylacetic acid to provide a fluorimetric end-point . A solid-phase enzyme-immunoassay has been described for 19-norethisterone, based upon the lla-hydrogen succinoyloxy derivative. ... 

Fig. 9.22 Three multistep C-C steroid bond cleavage P450 reactions (P450s llAl, 19A1, 51A1). Aromatization reactions catalyzed by P450 19A1 The three distinct steps are shown with the substrate testosterone. Other physiologically relevant substrates are androstenedione and 16a-hydroxytestosterone...

Cortisol and 21-deoxycortisol can by splitting of the side chain yield ll -hydroxyandrost-4-ene-3,17-dione, which may yield either adrenosterone or 11)8-hydroxytestosterone. The biosynthesis of testosterone is summarized in Fig. 8-14. 

There are several pathways for estrogen biosynthesis. Estradiol-17)8 is synthesized from testosterone and 19-hydroxytestosterone is an intermediate. Another pathway involves 19-hydroxytestosterone, which is in turn converted to 19-oxotestosterone. 19-Oxotestosterone may be either converted directly to estradiol-17)8 and acetate, or it may yield 19-carboxy-testosterone, which by decarboxylation yields 19-entostestosterone, an immediate precursor of estra-... 

Thus, in the Stein-Leventhal syndrome, the A pathway has preponderance over the A pathway, yielding precursors of testosterone. Without 11-hydroxytestosterone oxidation, testosterone (a precursor of estrogen) is not converted to estrogen. The enzyme defects just described are probably restricted to only part of the organ because, as already mentioned, normal levels of estrogens are found in patients with Stein-Leventhal syndrome, and wedge section cures the disease [91]. 

Scheme 12.11 Oxidation of testosterone, diclofenac, and phenacetin to yield 6 3-hydroxytestosterone (32), 4-hydroxydiclofenac (33) and acetaminophen (34), respectively.

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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