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Metabolism of Dihydrotestosterone in Human Liver: Importance of 3- and 3ß-Hydroxysteroid Dehydrogenase¹

Department of Pathology, Cornell University School of Medicine and Veterans Administration Medical Center, and the Department of Obstetrics and Gynecology, University of Kentucky College of Medicine, Lexington, Kentucky 40536

Address all correspondence and requests for reprints to: Dr. D. C. Collins, 204 Health Sciences Research Building, University of Kentucky Medical Center, Lexington, Kentucky 40536-0305.

	Abstract

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This study compared the enzyme activity of 3-hydroxysteroid dehydrogenase (3HSD) and 3ß-hydroxysteroid dehydrogenase (3ßHSD) in the human liver. 3HSD was found in both microsomal and cytosolic liver fractions. Contrary to that in rat liver, microsomal 3HSD activity was 12-fold higher than cytosolic 3HSD activity, and 3HSD was not inhibited by indomethacin (10 µmol/L). The rate of 5-dihydrotestosterone (DHT) reduction to 5-androstane-3,17ß-diol (3DIOL) by 3HSD was 2 times higher than the rate of 3DIOL oxidation to DHT. 3ßHSD was present primarily in the microsomal fraction of the human liver, and the rate of DHT reduction to 5-androstane-3ß,17ß-diol (3ßDIOL) by 3ßHSD was 3 times higher than the rate of 3ßHSD oxidation to DHT. When 3HSD and 3ßHSD activities were compared, the rate of DHT reduction by 3ßHSD was 3-fold lower than the rate of DHT reduction by 3HSD. No sex or age differences were found in either 3HSD or 3ßHSD activity. As the activity of DHT-metabolizing enzymes is not sex dependent, the sex differences in plasma levels of 3DIOL glucuronide probably reflect differences in DHT production rather than in DHT metabolism. Comparison of the activities of 3HSD, 3ßHSD, and androgen UDP-glucuronyl transferase suggests that the major pathway of DHT metabolism in human liver involves 3HSD reduction in the liver, followed by subsequent glucuronidation and clearance via the kidney.

	Introduction

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THE SYNTHESIS and metabolism of an active androgen, 5-dihydrotestosterone (DHT), takes place in extragonadal, androgen target tissues. For this reason, DHT is considered to be a paracrine or an autocrine hormone. DHT is synthesized from testosterone in an irreversible reaction catalyzed by the microsomal enzyme, 5-reductase. Modification of DHT at the 17ß-hydroxy or 3-keto position renders it inactive (Fig. 1). The reactions carried out by DHT-metabolizing enzymes are reversible, and the relative activities of these enzymes determines tissue exposure to the active androgen, DHT. One of the enzymes involved in DHT metabolism is 3-hydroxysteroid dehydrogenase (3HSD), which reduces DHT to 5-androstane-3,17ß-diol (3DIOL). Interestingly, 3HSD activity favors net production of DHT in certain tissues, such as the prostate (1). Inadequate metabolism of DHT by 3HSD may contribute to the development of prostate hyperplasia (1). Skin fibroblasts show different patterns of 3HSD activity in different skin areas (2). In nongenital skin, DHT formation from 3DIOL was approximately equal to DHT reduction to 3DIOL (2). However, in genital skin, the rate of DHT formation from 3DIOL was twice as high as DHT reduction (2). Little information is available about the regulation of 3HSD activity in other tissues. It is tempting to speculate that abnormal DHT metabolism may contribute not only to disorders such as prostate hyperplasia, but also to other androgen-related disorders such as acne and hirsutism.

View larger version (15K): [in this window] [in a new window]   Figure 1. Major pathways for DHT metabolism leading to glucuronyl metabolites. Minor pathways leading to sulfonated metabolites are not shown.

The equilibrium of reductive and oxidative activities of the hydroxysteroid dehydrogenases may be important in the regulation of intracellular levels of DHT. This study was designed to determine the activity and kinetic properties of 3HSD and 3ßHSD in the human liver. In addition, the activities of these enzymes were measured in liver homogenates from five females and five males to determine whether there are sex- or age-specific differences in the expression of these enzymes in the liver.

	Subjects and Methods

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Subjects

Liver samples from female (34–60 yr) and male (33–75 yr) organ donors were obtained from the National Disease Research Interchange (Philadelphia, PA). Samples were procured postmortem (within 5 h), snap-frozen upon removal, and stored at -70 C until used.

Chemicals

The radioactive androgens, [1,2-³H]3-DIOL (SA, 30.5 Ci/mmol) and [1,2,4,5,6,7-³H]DHT (SA, 119.6 Ci/mmol) were purchased from Amersham Pharmacia Biotech (Arlington Heights, IL). The nonradioactive steroids were obtained from Sigma Chemical Co. (St. Louis, MO) or Steraloids, Inc. (Wilton, NH). The purity of each androgen was confirmed by high pressure liquid chromatography. The protein assay reagents were obtained from Bio-Rad Laboratories, Inc. (Richmond, CA). All other chemicals were analytical grade.

Tissue fractionation

Liver samples were homogenized with a Polytron homogenizer (Brinkmann Instruments, Inc., Westbury, NY) in 4 vol ice-cold 50 mmol/L phosphate buffer, pH 7.4, containing 250 mmol/L sucrose and 0.5 mmol/L dithiothreitol. Aliquots of the liver homogenates were taken for analysis of 3HSD and 3ßHSD activities. The homogenates were centrifuged for 15 min at 12,000 x g, followed by ultracentrifugation of the supernatant at 100,000 x g for 60 min. The 100,000 x g pellets were rinsed once with 250 mmol/L sucrose and 50 mmol/L phosphate buffer, pH 7.4, and re-homogenized in 250 mmol/L sucrose and 50 mmol/L phosphate buffer, pH 7.4, with 20% glycerol. The microsomal and cytosolic fractions were stored at -80 C for up to 2 months with no significant change in enzyme activity. At the time of analysis, the viability of the microsomal fractions was confirmed by determining the activity of the microsomal marker enzyme, glucose-6-phosphatase, as described by Aronson and Touster (3), using 100 µmol glucose-6-phosphate as a substrate.

Enzyme kinetics

The enzyme activity studies were performed using liver homogenates or subcellular fractions. The K_m and V_max values were determined in the microsomal and cytosol fractions using the Michaelis-Menten equation with a nonlinear regression data analysis software program (Enzfitter 1.05, Biosoft, 1987). 3HSD activity was determined using tritiated substrates (DHT or 3DIOL). The incubation mixture (600 µL) contained 150,000 dpm of either [³H]DHT or [³H]3DIOL and cold androgens (final concentration, 0.1–20 µmol/L), an aliquot of the cell fraction (100 µg total homogenate protein, 150 µg cytosol protein, or 50 µg microsomal protein), 200 µmol/L NADP or NADPH, and 0.05% Tween-80 (vol/vol) in 25 mmol/L phosphate buffer, pH 7.4. The androgens were added to the tubes in ethanol solution before the assay, and the ethanol was evaporated before the other components of the incubation mixture were added. Control incubations were carried out without adding the cofactors, NADP or NADPH. Samples were incubated at 37 C in a shaking water bath for 0.5–5 min. DHT or 3DIOL was used as substrate at a concentration of 50 nmol/L (100 times the physiological concentration). The conditions of the assay used both cofactor (NADPH or NADP) and substrate at excess concentrations to ensure that product formation reflected maximal 3HSD activity and was linear with time and protein concentration.

The reaction products were extracted from the incubation mixture using reverse phase C₁₈ SPC columns. Aliquots of the incubation mixture (150 µL) were applied to the columns and eluted with 1.5 mL water, 0.5 mL hexane, and finally, 1.5 mL ethanol. All of the radioactivity was recovered in the ethanol eluate. The ethanol fractions were evaporated using a Speed-Vac evaporator (Savant Instruments, Farmingdale, NY), reconstituted in ethanol containing cold tracer (100 µg each of DHT, 3DIOL, and 3ßDIOL), and separated by high pressure liquid chromatography (Waters, Millipore Corp., Millford, MA) using a C₁₈ column (Waters, Millipore Corp.) and a mobile phase of acetonitrile-water (45:55) at a flow rate of 1 mL/min. The retention times for the androgens were: 3DIOL, 9.46; 3ß-DIOL, 7.32; and DHT, 10.95. The radioactivity in the eluted samples was quantitated using a Radio-Chromatography Detector (Radiomatic FLO-ONE Beta, Series A-500, Radiomatic Instruments & Chemical Co., Inc., Meriden, CT) and analyzed with the Radiomatic FLO-ONE Software program (Radiomatic Instruments & Chemical Co., Inc.).

3ßHSD activity was determined as described above, except that 3ßDIOL was the substrate for the oxidative reaction, and 150 µg microsomal protein, 450 µg cytosolic protein, or 100 µg total homogenate protein were used in the incubation.

Protein determination

Protein concentrations of the homogenates and cellular fractions were determined as described by Bradford (4), using BSA as a standard.

	Results

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Kinetic characteristics of 3HSD and 3ßHSD in liver

The K_m and maximum velocity (V_max) values of 3HSD and 3ßHSD for both the reduction of DHT and the oxidation of 3DIOL and 3ßDIOL in the microsomes and cytosol are shown in Table 1 for a 65-yr-old Caucasian male. A similar pattern of K_m constants and reductive and oxidative activities was noted in the other samples that were fractionated. 3HSD activity was expressed in both the microsomal and cytosolic fractions. The V_max value was 12-fold higher in the microsomes than in the cytosol for both the oxidative and reductive reactions. The K_m values for DHT and 3DIOL were similar in both cellular fractions. The V_max/K_m ratio represents the relative reaction velocity (see Table 1), assuming that the initial concentrations of the substrates, DHT and 3DIOL, are equal (see Table 1). This is, in fact, the physiological situation, as plasma levels of DHT and 3DIOL are approximately equal (5). The relative rate of DHT reduction was 2 times the relative rate of 3DIOL oxidation in the microsomes. In cytosol, the V_max/K_m ratios for reduction and oxidation were similar. Neither microsomal nor cytosolic 3HSD activity was inhibited by indomethacin at a concentration as high as 10 µmol/L (data not shown).

View this table: [in this window] [in a new window]   Table 1. Michaelis-Menten constants (Km), maximal velocities (Vmax), and Vmax/Km ratios of 3HSD and 3ßHSD in liver microsomes and cytosol of a 65-yr-old Caucasian male

Activity of 3HSD and 3ßHSD in liver homogenates from males and females

3HSD activity in liver homogenates from five male and five female subjects is shown in Fig. 2. In all subjects, the velocity of DHT reduction to 3DIOL was 2 times higher than the velocity of 3DIOL oxidation to DHT. There was no significant difference between the mean rate ± SE for 3HSD reduction in men (38.5 ± 16.9 pmol/min·mg protein) and women (38.3 ± 10.6; Table 2). 3HSD activity (DHT reduction) was 9.4–103.7 pmol/min·mg for men and 10.0–73.1 pmol/min·mg for women. Furthermore, no significant correlation was found between 3HSD activity and the age of the subjects.

View larger version (44K): [in this window] [in a new window]   Figure 2. 3HSD activity (picomoles per min/mg protein) in liver homogenates from five male and five female subjects. DHT (50 nmol/L) was the substrate for the reductive reaction (DHT3DIOL). 3DIOL (50 nmol/L) was the substrate for the oxidative reaction (3DIOLDHT).

View this table: [in this window] [in a new window]   Table 2. Mean activity (picomoles per min/mg ± SE) of 3HSD and 3ßHSD in liver homogenates from five male and five female subjects

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The need to understand the pathways for metabolism of DHT in human tissues was brought about by the long and unsuccessful search for a reliable biochemical test of androgen excess. The concentration of DHT in plasma does not correlate with the clinical symptoms of hyperandrogenism (6). Horton et al. (7) proposed that plasma levels of 3DIOL glucuronide reflected the formation and metabolism of DHT in extrahepatic, androgen target tissues, such as skin and prostate (7). However, only limited studies of the enzymes involved in DHT metabolism in human tissues other than skin and prostate have been performed, and the relative contributions of these tissues to plasma levels of androgen conjugates were not clearly established. In a recent study of human subjects, Duffy et al. (8) demonstrated that percutaneously applied DHT is more readily converted to 3DIOL than DHT infused iv, suggesting significant activity of 3HSD in skin. On the other hand, conversion of 3DIOL to 3DIOL glucuronide was more efficient after iv infusion of DHT than with percutaneous application. Giagulli et al. (9) reported that the plasma level of 3DIOL glucuronide was an order of magnitude higher after oral administration of testosterone compared to transdermal application. These observations suggested the importance of the splanchnic organs for androgen glucuronidation and support in vitro data obtained from several studies. Recent studies of in vitro androgen UDPGT activity revealed that androgen glucuronidation occurs almost exclusively in the liver (10, 11, 12, 13). These results from several different laboratories raise serious concerns about the hypothesis that plasma levels of 3DIOL glucuronide reflect exclusively androgen action and metabolism in extrahepatic tissues (8, 9, 10, 11, 12, 13).

The level of DHT in androgen target tissues is regulated mainly by 5-reductase and 3HSD. 3HSD was initially purified from rat liver cytosol, and subsequently, the gene was cloned from human liver and prostate (14, 15, 16). Although 3HSD activity from rat liver and rat and human prostate has been extensively characterized (17, 18, 19, 20), no comparative studies of the enzyme oxidative and reductive activities in human liver have been conducted.

We present here a comparative study of the kinetic properties of 3HSD and 3ßHSD involved in DHT metabolism in the human liver. 3HSD, the most active DHT-metabolizing enzyme, was present in both the microsomal and cytosol fractions. The V_max of microsomal 3HSD was 12-fold higher than that of cytosolic 3HSD. This is in contrast to rat liver, where cytosolic 3HSD was 10 times more active than microsomal 3HSD (18). Another distinctive feature was that 3HSD in the human was not sensitive to indomethacin, a strong inhibitor of 3HSD in the rat (18, 21). Our laboratory and others (18, 21) have shown that rat 3HSD possesses high affinity binding and sensitivity to inhibition by nonsteroidal antiinflammatory drugs. If human 3HSD was inhibited by nonsteroidal antiinflammatory drugs, significant clinical consequences would be expected. However, we found no inhibition of this enzyme activity even with a high concentration of indomethacin (10 µmol/L).

The reductive activity of 3HSD (DHT3DIOL) was 2 times higher than the oxidative activity (3DIOLDHT). This indicates that 3HSD in the human liver favors reduction of DHT to 3DIOL. Liver samples from both male and female subjects showed a wide range of values in 3HSD activity. However, the mean activity in men and women was not statistically different. This suggests that human 3HSD is not regulated by sex steroids. In contrast, rat liver 3HSD exhibits sexual dimorphic expression. The enzyme activity is elevated in female rat liver and appears to be under the control of estrogens (22). In addition, no change in 3HSD activity was found to be related to age in our samples.

3ßHSD activity was found primarily in the human liver microsomes and was 3-fold lower than the activity of microsomal 3HSD. DHT reduction to 3ßDIOL was 3 times higher than the oxidation of 3ßDIOL to DHT. This indicates that 3ßHSD in liver contributes to the clearance of DHT, but to a lesser extent than 3HSD. These in vitro observations support in vivo studies of the metabolic clearance and origin of DHT in humans (23). Mahoudeau et al. (23) also found that the ratio for in vivo conversion of DHT to 3DIOL was greater than that to 3ßDIOL, as we report here in the liver in vitro. In contrast, Dijkstra et al. (24) found that 3ßDIOL was the major product of DHT metabolism in the sebaceous glands in skin. This result is particularly interesting because plasma levels of 3ßDIOL have been reported to be 3-fold higher than plasma levels of 3DIOL in both men and women (5). There are at least two potential explanations for this observation. First, a tissue other than the liver may be the primary source for plasma 3ßDIOL (e.g. skin). Second, the clearance of 3ßDIOL may be much slower than the clearance of 3DIOL, perhaps due to the low affinity of UDP-glucuronyl transferase for 3ßDIOL. This is supported by the observation that plasma levels of 3ßDIOL glucuronide are lower than those of 3DIOL glucuronide (5). No sex or age differences in 3ßHSD activity were found in the human liver.

The scheme for DHT metabolism leading to formation of glucuronated metabolites in the human liver is shown in Fig. 3. The numbers represent calculated enzyme velocities (velocity = V_max/K_m x [S] with a physiological substrate concentration for males). The values for androgen UDPGT velocity were calculated from previous studies from our laboratory (13). The scheme was created using results from in vitro kinetic studies of enzyme activity in subcellular fractions. The values represent relative enzyme velocities in vitro and may not represent the in vivo state. A well controlled perfusion study would be required to determine in vivo dynamics.

View larger version (20K): [in this window] [in a new window]   Figure 3. Proposed scheme for DHT metabolism in human liver. The values are the enzyme velocities at a physiological concentration (Vmax/Km x [S] in femtomoles per min/mg protein).

	Footnotes

 
¹ This work was supported by NIH Grant R01-DK-41879 and the Department of Veterans Affairs.

Received January 28, 1999.

Revised May 19, 1999.

Accepted May 21, 1999.

	References

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