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Many central actions of testosterone (T) require the transformation of T into several metabolites including 5 alpha-dihydrotestosterone (5 alpha-DHT) and estradiol (E2). In birds as in mammals, 5 alpha-DHT and E2, alone or in combination, mimic most behavioral effects of T. The avian brain is, in addition, able to transform T into 5 beta-DHT, a metabolite which seems to be devoid of any behavioral or physiological effects, at least in the context of reproduction. By in vitro product-formation assays, we have analyzed the distribution, sex differences and regulation by steroids of the 3 main T metabolizing enzymes (aromatase, 5 alpha- and 5 beta-reductases) in the brain of the Japanese quail (Coturnix c. japonica) and the zebra finch (Taeniopygia guttata castanotis). In the hypothalamus of quail and finches, aromatase activity is higher in males than in females. It is also decreased by castration and increased by T. The activity of the 5 alpha-reductase is not sexually differentiated nor controlled by T. The 5 beta-reductase activity is often higher in females than in males but this difference disappears in gonadectomized birds and no clear effect of T can be observed at this level. The zebra finch brain also contains a number of steroid-sensitive telencephalic nuclei [e.g. hyperstriatum ventrale, pars caudale (HVc) and robustus archistriatalis (RA)] which play a key role in the control of vocalizations. These nuclei also contain T-metabolizing enzymes but the regulation of their activity is substantially different from what has been observed in the hypothalamus. Aromatase activity is for example higher in females than in males in HVc and RA and the enzyme in these nuclei is not affected by castration nor T treatment. In these nuclei, the 5 alpha-reductase activity is higher in males than in females and the reverse is true for the 5 beta-reductase. These sex differences in activity are not sensitive to gonadectomy and T treatment and might therefore be organized by neonatal steroids. We have been recently able to localize aromatase-immunoreactive (AR-ir) neurons by ICC in the brain of the quail and zebra finch. Positive cells are found in the preoptic area, ventromedial and tuberal hypothalamus. AR-ir material is found in the perikarya of cells and fills the entire cellular processes including axons. At the electron microscope level, immunoreactive material can clearly be observed in the synaptic boutons. This observation raises questions concerning the mode of action of estrogens produced by central aromatization of T.
J Steroid Biochem Mol Biol 1991
PMID:Testosterone metabolism in the avian hypothalamus. 195 58

Incubation of human testicular homogenates with [4-14C]pregnenolone gave substantial amounts of an unknown metabolite within 1 min, reaching plateau values of 17-23% of total radioactivity added within 5 min. Mass spectrometry of the metabolite showed it to be identical to the boar sex pheromone precursor androsta-5, 16-diene-3 beta-ol (ADL). In cell cultures the major source of ADL and its dehydrogenated metabolite androsta-4, 16-diene-3-one (ADN) was the Leydig cell. In rat and monkey testicular homogenates 16-ene-synthetase activity, a prerequisite for the synthesis of ADL and ADN, was completely lacking, limiting the presence of 16-androstenes to boars and men. In contrast to boars, however, in the human testis no 5 alpha-reductase activity was found and consequently no 5 alpha-reduced-16-androstenes, e.g. androstenol (AL, musk like) and androstenone (AN, urine like), known sex pheromones in pigs. As both sex pheromones have been identified in urine, plasma, sweat and saliva of men and (especially hirsute) women we hypothesize that AL and AN are synthesized from ADL via ADN peripherically in tissues rich in 5 alpha-reductase, i.e. skin, axillary sweat glands and probably also the salivary glands. So far, there is some evidence that both sex pheromones may have similar functions in humans as in boars.
J Steroid Biochem Mol Biol 1991
PMID:16-Ene-steroids in the human testis. 195 60

The central nervous system (CNS) is considered a target structure for the action of all the classes of hormonal steroids produced by the organism. Well-characterized genomic and less well-understood membrane mechanisms of action are probably involved in the steroid modulation of brain activities. Moreover, some classes of steroids need to be converted into "active" metabolites before interacting with their effector systems. In particular, testosterone (T) exerts many of its effects after conversion to 5 alpha-dihydrotestosterone (DHT) and estrogens. The CNS possesses both the 5 alpha-reductase, the enzyme which produces DHT and the aromatase which transforms T into estrogens; however, the relative role and distribution of these enzymes in the various structural components of the CNS has not been clarified so far. The 5 alpha-reductase has been found to be present in high concentrations in brain white matter structures because these are particularly rich in myelin membranes, to which the enzymatic activity appears to be associated. This membrane localization might suggest a possible involvement of steroidal 5 alpha-reduced metabolites in membrane-mediated events in the CNS. Moreover, the distribution of 5 alpha-reductase was studied in neurons, astrocytes and oligodendrocytes isolated from the brain of male rats by density gradient ultracentrifugation, as well as in neurons and glial cells grown in culture. The aromatase activity was also evaluated in neurons and glial cells grown in culture and in isolated oligodendrocytes. Among the three cell types isolated, neurons appear to be more active than oligodendrocytes and astrocytes, respectively, in converting T into DHT. Also, in cell culture experiments, neurons are more active in forming DHT than glial cells. Only neurons possess aromatase activity, while glial cells are apparently unable to aromatize T.
J Steroid Biochem Mol Biol 1991
PMID:Testosterone metabolism in brain cells and membranes. 195 65

Rabbit epiphyseal cartilage tissue has been shown to convert testosterone (T) to dihydrotestosterone (DHT). In this report, the metabolic conversion of T into DHT is shown to be age-dependent, being most active in cartilage from animal at the age of gonadal maturation. Human cartilage from newborn and prepubertal children is also shown to convert T into DHT and--to a lesser extent--to estradiol. Low concentrations of DHT and 17 beta-estradiol (E2) (10(-11)-10(-9) M) were also shown to stimulate in vitro cartilage cells from boys and girls respectively. As previously shown for cultured rabbit chondrocytes, the stimulating effects of both hormones on human chondrocytes was age-dependent. Cartilage cells derived from children up to one year old did not respond, while cells from boys and girls in the early phase of puberty responded best. These data indicate that human cartilage tissue in vivo, contains both 5 alpha-reductase and aromatase activities during post-natal skeletal growth. Androgens may act on cartilage after their metabolic conversion to estrogens. The mechanism of age-dependency of both cartilage androgen enzymatic activities and chondrocyte responsiveness to sex steroids in vitro remains to be explained.
J Steroid Biochem Mol Biol 1991
PMID:Age-dependent responsiveness of rabbit and human cartilage cells to sex steroids in vitro. 195 68

H69AR is a multidrug-resistant small cell lung cancer cell line derived from a drug-sensitive cell line, H69, by selection in doxorubicin. It is cross-resistant to a wide variety of natural product-type antineoplastic agents but does not overexpress P-glycoprotein. In the present study, the levels of GSH and GSH-related enzymes in the H69AR cell line were determined and compared with those found in H69 cells. Unlike other drug-resistant cell lines, GSH levels were diminished 6-fold in H69AR cells (0.67 +/- 0.28 microgram/mg of protein), compared with H69 cells (4.23 +/- 1.17 micrograms/mg of protein) (p less than 0.01). This unusually low level of GSH may explain the pronounced collateral sensitivity of H69AR cells to buthionine sulfoximine (BSO), an inhibitor of the rate-limiting enzyme in GSH biosynthesis (ID50 of 4.4 microM BSO for H69AR cells versus ID50 of 300 microM BSO for H69 cells). BSO did not enhance doxorubicin cytotoxicity in the H69AR cell line, despite further depletion of GSH. GSH-reductase (EC 1.6.4.2) activity was elevated 2-fold in H69AR cells, compared with sensitive H69 cells (75.34 +/- 14.94 versus 38.62 +/- 5.06 nmol of NADPH/min/mg of protein) (p less than 0.05). Both selenium-dependent and -independent GSH-peroxidase (EC 1.11.1.9) activities were unchanged in the resistant H69AR cell line, compared with its parent cell line. gamma-Glutamyl transpeptidase (EC 2.3.2.2) activity was 5-fold elevated in H69AR cells, compared with H69 cells (2.50 +/- 0.44 versus 0.46 +/- 0.21 nmol of p-nitroaniline/min/mg of protein) (p less than 0.01), whereas GSH-S-transferase (EC 2.5.1.18) activity was 10-fold higher (201.98 +/- 43.62 versus 19.77 +/- 1.72 nmol of 1-chloro-2,4-dinitrobenzene/min/mg of protein in H69AR and H69 cells, respectively) (p less than 0.01). The GSH-S-transferases from both cell lines were purified by affinity chromatography and immunoblot analysis identified the GSH-S-transferases as belonging to the anionic pi class. GSH-S-transferases from the mu or alpha classes were not detectable in either cell line. In conclusion, marked differences in GSH levels and the activities of three of four GSH-related enzymes were observed between the multidrug-resistant H69AR cell line and its parent cell line. Further study is required to determine whether these changes are causally related to the development of drug resistance in this model system.
Mol Pharmacol 1990 Feb
PMID:Alterations in glutathione and glutathione-related enzymes in a multidrug-resistant small cell lung cancer cell line. 196 21

The cytochrome P-450 monooxygenase enzymes, NADPH-reductase and form 2, were demonstrated immunohistochemically in hamster tracheal epithelium that was regenerating after mechanical injury. Bromodeoxyuridine (BrdU), a thymidine analogue, was used to map the location and extent of the wound sites between 8 and 144 h post-injury. In the control and non-wounded areas of the epithelium, the secretory cells were labelled for the monooxygenase enzymes. Label was heaviest in the apical cytoplasm of these columnar cells. At 8 h, secretory cells at the wound margins migrated to cover the wound sites, becoming progressively flattened. Reaction product for monooxygenase enzymes was strong in these flat cells but immunolabelling for BrdU was very low. At 24 h many cells at the wound sites were labelled for BrdU (indicative of a high rate of cell division). Some cells were labelled for monooxygenase but many were not stained at this time. At 48 and 72 h post-injury, none of the cells within the wound sites (regenerating epithelium) were stained. Immunochemical labelling for the monooxygenase enzymes was restored to the nascent secretory cells as they differentiated in the wound sites, beginning at 96 h post-injury. Labelling was stronger at 120 and 144 h post-injury, comparable to that in the control epithelium. The observations suggest that the monooxygenase enzymes were retained by the secretory cells in the wound sites before they divided but were lost from their progeny. Then, the temporal sequence of monooxygenase expression was similar to the pattern of differentiation of nascent secretory cells during fetal development of the tracheal epithelium.
Virchows Arch B Cell Pathol Incl Mol Pathol 1990
PMID:Immunohistochemical demonstration of cytochrome P-450 monooxygenase in regenerating tracheal epithelium: a recapitulation of fetal development. 198 Jan 74

In order to characterize the main enzymatic systems involved in androgen and estrogen formation as well as metabolism in ZR-75-1 human breast cancer cells, incubation of intact cells was performed for 12 or 24 h at 37 degrees C with tritiated estradiol (E2), estrone (E1), androst-5-ene-3 beta, 17 beta-diol (5-ene-diol), dehydroepiandrosterone (DHEA), testosterone (T), androstenedione (4-ene-dione), dihydrotestosterone (DHT) or androsterone (ADT). The extra- and intracellular steroids were extracted, separated into free steroids, sulfates and non-polar derivatives (FAE) and identified by HPLC coupled to a Berthold radioactivity monitor. Following incubation with E2, 5-ene-diol or T, E1, DHEA and 4-ene-dione were the main products, respectively, thus indicating high levels of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD). When 4-ene-dione was used, on the other hand, a high level of transformation into 5 alpha-androstane-3,17-dione (A-dione), Epi-ADT and ADT was found, thus indicating the presence of high levels of 5 alpha-reductase as well as 3 alpha- and 3 beta-hydroxysteroid dehydrogenase. Moreover, some T was formed, due to oxidation by 17 beta-HSD. No estrogen was detected with the androgen precursors T or 4-ene-dione, thus indicating the absence of significant aromatase activity. Moreover, significant amounts of sulfates and non-polar derivatives were found with all the above-mentioned substrates. The present study shows that ZR-75-1 human breast cancer cells possess most of the enzymatic systems involved in androgen and estrogen formation and metabolism, thus offering an excellent model for studies of the control of sex steroid formation and action in breast cancer tissue.
J Steroid Biochem Mol Biol 1991 Feb
PMID:Multiple steroid metabolic pathways in ZR-75-1 human breast cancer cells. 200 38

The conversion of testosterone to dihydrotestosterone (DHT) by 5 alpha-reductase and the interconversion between DHT and 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) by 3 alpha-hydroxy-steroid oxidoreductase (3 alpha-HSOR) were studied in fibroblasts derived from the genital skin of 22 males and 6 females, and from the nongenital skin of 19 males and 9 females with normal gonadal function. The formation of DHT from testosterone (5 alpha-reduction) was significantly greater in fibroblasts from genital skin than in those from nongenital skin in both males (2.15 +/- 1.43 vs 0.81 +/- 0.46 pmol/mg protein/h, mean +/- SD, P less than 0.001) and females (2.52 +/- 1.99 vs 0.69 +/- 0.18, P less than 0.01). Furthermore, DHT formation from 3 alpha-diol (3 alpha-HSOR oxidation) was also significantly greater in genital skin fibroblasts than in nongenital skin fibroblasts of males (5.47 +/- 3.37 vs 2.52 +/- 1.74 pmol/mg protein/h, P less than 0.01). However, the degradation of DHT to 3 alpha- and/or 3 beta-diol (3 alpha- and/or 3 beta-HSOR reductions) was not different between genital and nongenital skin fibroblasts of either males or females. Respective ratios of DHT formation to DHT degradation (5 alpha-reduction/3 alpha-HSOR reduction, 3 alpha-HSOR oxidation/3 alpha-HSOR reduction) were also significantly greater (P less than 0.002) in genital skin fibroblasts than in nongenital skin fibroblasts of males. On the other hand, both DHT formation and degradation were not different between male and female genital skin fibroblasts. These results suggest that the increased production of DHT in genital compared to nongenital skin results from increased 5 alpha-reduction and 3 alpha-HSOR oxidation.
J Steroid Biochem Mol Biol 1991 Feb
PMID:DHT formation and degradation in cultured human skin fibroblasts: DHT accumulation in the genital skin. 200 44

The potential biosynthetic capacity of testicular hormones was studied in immature, pubertal and aging guinea-pig. In their sexual development towards puberty, changes in the relationship of the steroids involved in the steroidogenic pathways were observed. The testosterone/androstenedione ratio changes markedly, showing an important increase with pubertal proximity. The testosterone in equilibrium androstenedione sequence, reversibly catalyzed by 17 beta-hydroxysteroid oxidoreductase (17 beta-oxido-reductase), clearly shifted towards androstenedione in immature animals irrespective of the precursor utilized. Post-pubertal animals showed a greater enzymatic activity in the 5-ene and 4-ene testicular synthesis pathways, testosterone production being greatest. In the aging animal, hormonal biosynthetic capacity falls. Reversion of the 17 beta-oxido-reductase activity could be one of the mechanisms responsible for the decrease in testosterone, as in immature guinea-pigs. In order to investigate the in vitro steroidogenic capacity of glands at different ages, minces of testicular tissue were incubated with labelled precursors. The studies were conducted in triplicate at 35 degrees C. For equal quantities of incubated tissue the non-metabolized amount of [3H]pregnenolone and [14C]progesterone, utilized as precursors, was different in post-pubertal and senescent animals: 55.7 +/- 3 vs 59.3 +/- 2.3% (P less than 0.01) for pregnenolone, and 50.1 +/- 3.3 vs 56.3 +/- 2.9% (P less than 0.01) for progesterone, respectively. Testosterone production was 12 +/- 2% in adult and 6.7 +/- 2.7% in senescent animals (P less than 0.01). The testosterone/androstenedione ratio was not significantly different in post-pubertal and senescent animals: 2.8 +/- 0.5 vs 2.4 +/- 0.4, but consistently higher than found in immature animals: 0.3 +/- 0.1. The lesser potential capacity of the aging tissue to synthesize testosterone could be explained by a decline in the glands capacity to metabolize the hormonal precursors.
J Steroid Biochem Mol Biol 1991 Feb
PMID:Biosynthesis of testicular steroids in the immature, adult and senescent guinea-pig. 200 45

16-Dehydroprogesterone reductase (16-DHPR) activity was present in cell extracts of Eubacterium sp. strain 144 only when the organism was grown in the presence of steroids containing a delta 16-17 double bond and C-20-ketone. Cells grown with 16-dehydropregnenolone contained 16-DHPR activity but lacked delta 4-5-3-keto steroid reductase activity. Pyruvate or sodium dithionite served as electron donors for 16-DHPR and both reactions required methyl viologen as an electron carrier. Neither NADH nor NADPH, with or without flavin nucleotides, were used by 16-DHPR. Enzyme activity was detected in the cytoplasmic fraction (40%) and membrane fraction (20%) of crude cell extracts, but 40% of the activity was unaccounted for following ultracentrifugation. 16-DHPR activity was unaffected by pH in potassium phosphate buffer over the range 5.0 to 8.5, but was inhibited by Tris-HCl above pH 7.0. 16-DHPR activity was inhibited by sulfhydryl reagents, but inhibitors of electron transport reactions or metal chelators did not affect the enzyme.
J Steroid Biochem Mol Biol 1991 Feb
PMID:Characteristics of 16-dehydroprogesterone reductase in cell extracts of the intestinal anaerobe, Eubacterium sp. strain 144. 200 47


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