Thiazolidinediones but Not Metformin Directly Inhibit the
Steroidogenic Enzymes P450c17 and 3
-Hydroxysteroid
Dehydrogenase*
Wiebke
Arlt
,
Richard J.
Auchus§, and
Walter L.
Miller
¶
From the
Department of Pediatrics and the Metabolic
Research Unit, University of California, San Francisco, California
94143-0978 and the § Department of Medicine, University of
Texas, Southwestern Medical Center, Dallas, Texas 75390-8857
Received for publication, January 2, 2001, and in revised form, February 6, 2001
 |
ABSTRACT |
Androgen biosynthesis requires
3
-hydroxysteroid dehydrogenase type II (3
HSDII) and the
17
-hydroxylase and 17,20-lyase activities of cytochrome P450c17.
Thiazolidinedione and biguanide drugs, which are used to increase
insulin sensitivity in type 2 diabetes, lower serum androgen
concentrations in women with polycystic ovary syndrome. However, it is
unclear whether this is secondary to increased insulin sensitivity or
to direct effects on steroidogenesis. To investigate potential actions
of these drugs on P450c17 and 3
HSDII, we used "humanized yeast"
that express these steroidogenic enzymes in microsomal environments.
The biguanide metformin had no effect on either enzyme, whereas the
thiazolidinedione troglitazone inhibited 3
HSDII
(KI = 25.4 ± 5.1 µM) and both
activities of P450c17 (KI for 17
-hydroxylase,
8.4 ± 0.6 µM; KI for
17,20-lyase, 5.3 ± 0.7 µM). The action of
troglitazone on P450c17 was competitive, but it was mainly a
noncompetitive inhibitor of 3
HSDII. The thiazolidinediones
rosiglitazone and pioglitazone exerted direct but weaker inhibitory
effects on both P450c17 and 3
HSDII. These differential effects of
the thiazolidinediones do not correlate with their effects on insulin
sensitivity, suggesting that distinct regions of the thiazolidinedione
molecule mediate these two actions. Thus, thiazolidinediones inhibit
two key enzymes in human androgen synthesis contributing to their
androgen-lowering effects, whereas metformin affects androgen synthesis
indirectly, probably by lowering circulating insulin concentrations.
 |
INTRODUCTION |
The first and rate-limiting step in the biosynthesis of all
steroid hormones is the conversion of cholesterol to pregnenolone by
the mitochondrial cholesterol side chain cleavage enzyme, P450scc, which is thus the quantitative regulator of steroidogenesis (1). The
qualitative regulator is microsomal P450c17, which sequentially catalyzes both 17
-hydroxylase and 17,20-lyase activities (2-4). In
the absence of either activity of P450c17, adrenal pregnenolone is
directed toward the biosynthesis of mineralocorticoids. When only
17
-hydroxylase activity is present, the resulting
17
-hydroxypregnenolone (17-Preg)1 is converted to
cortisol; when both the 17
-hydroxylase and 17,20-lyase activities
are present, the C19 steroid dehydroepiandrosterone (DHEA)
is produced. DHEA then can be converted to androstenedione by
3
-hydroxysteroid dehydrogenase type II (3
HSDII), and
androstenedione is converted to testosterone and estradiol by isozymes
of 17
-hydroxysteroid dehydrogenase and by aromatase (P450aro) (5,
6). The biosynthesis of all sex steroids proceeds through DHEA because
human P450c17 does not convert 17
-hydroxyprogesterone (17OHP) to
androstenedione (4, 7, 8). Thus P450c17 and 3
HSDII are key enzymes
required for the synthesis of all androgens (Fig.
1A).

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Fig. 1.
Structures and chemical reactions.
A, only two enzymes are needed to catalyze the steroid
biosynthetic reactions shown, P450c17 and 3 HSDII. The
17 -hydroxylase activity of P450c17 catalyzes the conversion of
pregnenolone to 17-Preg and of progesterone to 17OHP with equivalent
Km and Vmax values (8); the
17,20-lyase activity of P450c17 catalyzes the conversion of 17-Preg to
DHEA with much lower efficiency (8). 3 HSDII converts pregnenolone to
progesterone, 17-Preg to 17OHP, and DHEA to androstenedione, all with
equivalent Km and Vmax values
(21). In this study, 3 HSD activity is measured as conversion of
pregnenolone to progesterone, 17 -hydroxylase activity is measured as
conversion of progesterone to 17OHP, and 17,20-lyase activity is
measured as conversion of 17-Preg to DHEA. B, structures of
the inhibitors used. Top, metformin, shown as the
hydrochloride; middle, the thiazolidinedione nucleus (note
the R group in the ether linkage); bottom, structures of the
thiazolidinedione R group in troglitazone (TRO),
rosiglitazone (ROSI), and pioglitazone
(PIO).
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Polycystic ovary syndrome (PCOS) is the most frequent cause of female
infertility, affecting ~5-10% of women of reproductive age (9, 10).
The insulin-sensitizing drugs metformin and troglitazone decrease
hyperandrogenemia and increase fertility in women with PCOS (11-14).
These agents might decrease circulating androgens indirectly by
lowering insulin levels, which may secondarily inhibit steroidogenesis
by an unknown mechanism. Alternatively, metformin and troglitazone also
might inhibit steroidogenic enzymes directly (12). Metformin and
troglitazone are members of two fundamentally different drug families
(Fig. 1B). Metformin, a biguanide, decreases hepatic
gluconeogenesis and enhances peripheral glucose uptake, either
secondarily by alleviating glucose toxicity (15) or possibly by
inhibiting complex 1 of the mitochondrial respiratory chain (16, 17).
Troglitazone, a thiazolidinedione drug, decreases both hepatic
gluconeogenesis and peripheral insulin resistance, probably through its
action as a ligand for the nuclear peroxisome proliferator-activated
receptor
(PPAR
) (18-20).
To determine whether metformin or troglitazone inhibits either P450c17
or 3
HSDII, and if so by what mechanism, we examined the actions of
these two drugs using our humanized yeast expression system (8, 21), in
which individual human steroidogenic enzymes are examined in native
microsomal environments without interfering factors that are often
present in whole-cell experiments.
 |
EXPERIMENTAL PROCEDURES |
Drug Preparations--
Reagent-grade metformin was purchased
from Sigma and dissolved in water; reagent-grade troglitazone, a
generous gift of Dr. Andrea Dunaif (Harvard University), was dissolved
in 100% Me2SO. Tablets of troglitazone,
rosiglitazone, and pioglitazone were purchased as Rezulin
(Parke-Davis), Avandia (Lilly), and Actos (Smith Kline Beecham),
respectively, and were dissolved in 100% Me2SO and
centrifuged to remove insoluble tablet material. The chemical
equivalence and purity of the troglitazone solutions prepared from
reagent-grade powder and tablets were confirmed by liquid
chromatography/mass spectrometry. Reagent-grade metformin and
troglitazone were used in all experiments except for the comparison of
troglitazone to rosiglitazone and pioglitazone in which troglitazone prepared from tablets was used to control for any variations in preparation.
Expression Vectors and Yeast Microsome
Preparation--
Saccharomyces cerevisiae strain W303B (22)
was transformed by the lithium acetate procedure (23) with the yeast
expression vector V10 (22) containing the cDNA sequences for human
P450c17 or 3
HSDII as described (8, 21). For P450c17 transformation, we cotransformed the yeast cultures with the vector pYcDE2 (24) expressing human P450 oxidoreductase cDNA (8). Yeast was grown, microsomes were prepared, and the microsomal P450 content was measured
as described (8).
Yeast Enzyme Assays--
Yeast microsomes were incubated in the
presence and absence of various concentrations of thiazolidinediones or
metformin added in 4 µl of Me2SO or water to 196 µl of
50 mM potassium phosphate buffer (pH 7.4). Enzymatic assays
were performed with 0.5-4 µM progesterone or
17
-hydroxypregnenolone for P450c17 activities and 1-20
µM pregnenolone for 3
HSDII activity. Each reaction
also contained 20,000 cpm of [14C]pregnenolone (55.4 mCi/mmol) (Amersham Pharmacia Biotech) for analysis of 3
HSDII
activity, 20,000 cpm of [14C]progesterone (55.4 mCi/mmol,
PerkinElmer Life Sciences) for 17
-hydroxylase activity, or 50,000 cpm of [3H]17-Preg (21.1 Ci/mmol, PerkinElmer Life
Sciences) for 17,20-lyase activity. Catalysis was initiated by adding 1 mM NADPH for P450c17 or 1 mM NAD+
for 3
HSDII activity, and assays were done in the linear time range
of the enzymatic reaction. Assays of 17,20-lyase activity were
performed with and without addition of purified recombinant human
cytochrome b5 (PanVera, Madison, WI) in 10-fold
molar excess to the total P450 content of the microsomes.
Steroids were extracted from the reaction mixtures with 400 µl of
ethyl acetate/isooctane (1:1) concentrated by evaporation under
continuous nitrogen flow and assayed by thin layer chromatography on
phosPE SIL G/UV silica gel plates (Whatman) using 3:1
chloroform/ethyl acetate as the solvent system (8, 25). The
radiolabeled steroids were quantified by phosphorimaging analysis on a
Storm 860 PhosphorImager (Molecular Dynamics, Sunnyvale, CA). All
assays were performed in triplicate, and data are presented as
means ± S.D. Kinetic behavior was approximated as a
Michaelis-Menten system, and data were plotted as described by
Lineweaver and Burk and by Dixon and Webb (26).
KI values were calculated from the equation for
competitive inhibition, Vapp = Vmax × [S]/(Km (1 + [I]/KI) + [S]), whereas data from
noncompetitive-competitive inhibition were approximated by the formula
for generic inhibition, Vapp = Vmax/(1 + [I]/KI) at each
[S] (27). Data fitting was carried out by LEONORA version 1.0 for
analysis of steady-state enzyme kinetics (27).
Cell Culture Enzyme Assay--
COS-1 monkey kidney cells were
grown as monolayers in 10-cm Petri dishes in 10 ml of Dulbecco's
modified Eagle's medium-H21 containing 4.5 g/liter glucose, 10% fetal
bovine serum, 100 IU/ml penicillin, and 0.1 mg/ml streptomycin. For
transient transfection, COS-1 cells were grown to 80% confluence and
split into six-well plates 24 h prior to transfection. Plasmid
pcDNA3 containing the wild-type human P450c17 cDNA (28) was
transfected into COS-1 cells at ~60% confluence using the calcium
phosphate/DNA coprecipitation method. Thirty-six hours after
transfection, cells were incubated with 2 ml of fresh Dulbecco's
modified Eagle's medium-H21 containing 20,000 cpm
[14C]progesterone and 0-100 µM
troglitazone; each troglitazone concentration was added in 10 µl of
Me2SO to triplicate wells. The steroids then were extracted
with 8 ml of ethyl acetate/isooctane (1:1), concentrated, and analyzed
as described above for the microsomal assays. Transfection efficiency
was monitored by cotransfecting COS-1 cells with the pRL-CMV plasmid
(Promega, Madison, WI) containing the Renilla luciferase
gene driven by the cytomegalovirus promoter. After removing the
medium, the cells were lysed and assessed for luciferase activity by
the dual luciferase reporter assay system (Promega).
 |
RESULTS |
Effects of Metformin and Troglitazone on P450c17--
Both
17
-hydroxylase and 17,20-lyase activities require the interaction of
P450c17 with its electron donor P450 oxidoreductase (OR); 17,20-lyase
activity is enhanced further by allosteric interaction of the
P450c17-OR complex with cytochrome b5 (8).
Microsomes from yeast expressing human P450c17 cDNA and OR catalyze
the conversion of pregnenolone to 17-Preg and of progesterone to 17OHP
equally well, but the 17,20-lyase reaction is 100 times more efficient with 17-Preg as the substrate than with 17OHP (7, 8). Thus, 17
-hydroxylase activity was measured as the conversion of
progesterone to 17OHP, because this product is not metabolized further,
and 17,20-lyase activity was measured as the conversion of 17-Preg to
DHEA in the presence of exogenously added cytochrome
b5 (8, 21).
Concentrations of metformin up to 100 µM did not inhibit
either activity of P450c17, but troglitazone readily inhibited both activities of P450c17 (Fig. 2). At a
substrate concentration of 1 µM progesterone,
troglitazone inhibited 17
-hydroxylase activity with an
IC50 of 12 µM, and at 1 µM
17-Preg, troglitazone inhibited 17,20-lyase activity with an
IC50 of 11 µM. These 1 µM
steroid-substrate concentrations are above the apparent
Km of about 0.5 µM for both the
17
-hydroxylase reaction and the 17,20-lyase reaction in this system
(8). The presence or absence of cytochrome b5 did not affect the IC50 of the lyase reaction (data not
shown). Thus, the inhibitory effect of troglitazone on 17,20-lyase
activity does not depend on interaction with cytochrome
b5. Kinetic analysis using both the
Lineweaver-Burk method (1/V plotted against 1/S) and the Dixon method (1/V plotted against inhibitor
concentration) revealed a competitive mode of inhibition with
KI values of 8.4 ± 0.6 µM for
17
-hydroxylase activity and of 5.3 ± 0.7 µM for
17,20-lyase activity (Fig. 3). Thus,
troglitazone inhibits both activities of P450c17 by the same
mechanism.

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Fig. 2.
Effect of metformin and troglitazone on the
differential activities of human P450c17. A,
17 -hydroxylase activity. Microsomes prepared from yeast coexpressing
human P450c17 and human P450 oxidoreductase were incubated with 1 µM [14C]progesterone (Prog) and
0-100 µM metformin (MET) and troglitazone
(TRO). 17 -Hydroxylase activity was assessed as the
conversion rate of [14C]progesterone to 17OHP.
B, 17,20-lyase activity. Microsomes coexpressing P450c17 and
OR were incubated with 1 µM 17-Preg and 0-100
µM metformin and troglitazone. 17,20-Lyase activity was
assessed as the conversion rate of
[3H]17 -hydroxypregnenolone to DHEA. Each data point
represents the mean ± S.D. of triplicate determinations.
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Fig. 3.
Kinetic analysis of the mode of inhibition of
P450c17 activities by troglitazone (TRO).
Lineweaver-Burk plots of 17 -hydroxylase activity (A) and
17,20-lyase activity (B) and Dixon plot of 17 -hydroxylase
activity (C) in the absence and presence of troglitazone
(0-20 µM) and with 0.5, 1, 2, and 4 µM
[14C]progesterone (Prog) and 17-Preg for the
assessment of 17 -hydroxylase and 17,20-lyase activity, respectively.
Incubations were carried out with yeast microsomes (40 µg of total
protein) coexpressing human P450c17 and human P450 oxidoreductase. Each
data point represents the mean ± S.D. of triplicate
determinations.
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The inhibitory effect of troglitazone was seen both in the yeast
microsome system and in mammalian cells expressing P450c17. Troglitazone inhibited 17
-hydroxylase activity in transiently transfected COS-1 cells in a dose-dependent fashion with an
IC50 of 16 µM (Fig.
4), which is very similar to the
IC50 of 12 µM observed in yeast
microsomes.

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Fig. 4.
Inhibition of
17 -hydroxylase activity by troglitazone
(TRO) in whole cells (solid line) and
in yeast microsomes (dotted line). COS-1 cells
transiently expressing human P450c17 and yeast microsomes expressing
both P450c17 and P450 oxidoreductase were incubated with
[14C]progesterone (Prog), and
17 -hydroxylase activity was determined as the conversion rate of
[14C]progesterone to 17OHP. Each data point represents
the mean ± S.D. of triplicate determinations.
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Effects of Metformin and Troglitazone on 3
HSDII
Activity--
The two forms of human 3
HSD are catalytically
equivalent (29, 30). Because 3
HSDII is the only form expressed in
human adrenals and gonads (30), we examined the potential inhibitory effects of metformin and troglitazone on this isozyme. We assayed 3
HSD activity in microsomes from yeast transformed with an
expression vector for human 3
HSDII. Because all three substrates for
3
HSD (pregnenolone, 17-Preg, and DHEA) have the same apparent
Km values and similar Vmax
values when analyzed in this yeast expression system (21), we measured
the conversion of pregnenolone to progesterone, which reflects the rate
of conversion of DHEA to androstenedione.
Metformin had no effect on 3
HSDII activity, but troglitazone
inhibited 3
HSDII activity in a dose-dependent fashion
with an IC50 of 24 µM (Fig.
5). To determine the mechanism by which troglitazone inhibited 3
HSDII activity we performed Lineweaver-Burk and Dixon kinetic analyses. In contrast to the competitive inhibition of P450c17, Lineweaver-Burk plots showed that troglitazone inhibited 3
HSDII activity by a noncompetitive mode with a
KI of 25.4 ± 5.1 µM (Fig.
6A). Pure noncompetitive
enzymatic competition yields a linear dose-response curve in Dixon
analysis (26). However, instead of showing a linear curve, Dixon plots
of 3
HSDII inhibition by troglitazone yielded a hyperbolic curve
(Fig. 6B). This indicates that there are separate modes of
inhibition occurring at low inhibitor concentrations (a more potent
noncompetitive mode) and at high inhibitor concentrations (an
additional competitive mode). Such behavior might be explained by the
simultaneous binding of two molecules of inhibitor to one molecule of
enzyme (26). Thus, the mode by which troglitazone inhibits 3
HSDII
activity is clearly different from the mode by which it inhibits
P450c17.

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Fig. 5.
Effect of metformin and troglitazone on
3 HSDII activity. Microsomes prepared from
yeast expressing human 3 HSDII were incubated with 5 µM
[14C]pregnenolone (Preg) and 0-100
µM metformin (MET) and troglitazone
(TRO). 3 HSDII activity was assessed as the conversion
rate of [14C]pregnenolone to progesterone
(Prog). Each data point represents the mean ± S.D. of
triplicate determinations.
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Fig. 6.
Kinetic analysis of the mode of inhibition of
3 HSDII activity by troglitazone
(TRO). Lineweaver-Burk plot (A) and
Dixon plot (B) of 3 HSDII activity. Incubations were
carried out with yeast microsomes (40 µg total protein) expressing
human 3 HSDII in the absence and presence of troglitazone (0-60
µM) with 1, 5, 10, and 20 µM
[14C]pregnenolone (Preg). Each data point
represents the mean ± S.D. of triplicate determinations.
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Comparison of Troglitazone to Other Thiazolidinediones--
To
determine whether the inhibitory effects of troglitazone are unique to
this particular drug or are a general characteristic of
thiazolidinedione compounds, we compared the effects of troglitazone on
P450c17 and 3
HSDII activities to those of two other
thiazolidinediones, rosiglitazone and pioglitazone (Fig.
7). Rosiglitazone inhibited both the
17
-hydroxylase (IC50 = 86 µM) and the
17,20-lyase (IC50 = 90 µM) activities of
P450c17 and also inhibited 3
HSDII activity (IC50 = 54 µM) but to a considerably lesser extent than troglitazone (IC50 = 10, 16, and 20 µM, respectively).
Pioglitazone had minimal inhibitory effects on all three enzymatic
activities with IC50 values of >100 µM. A
summary of all the inhibition constants of the three thiazolidinediones
on the three enzymatic activities is shown in Table
I. Thus, the potential for direct
inhibition of both P450c17 and 3
HSDII seems to be a general
characteristic of thiazolidinedione drugs, but the substantial
variations in their inhibitory effects indicate that minor changes in
the thiazolidinedione structure have major effects on their actions as
inhibitors of steroidogenic enzymes.

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Fig. 7.
Differential inhibition of P450c17 and
3 HSDII by thiazolidinediones.
A, 17 -hydroxylase activity. Microsomes prepared
from yeast coexpressing human P450c17 and human P450 oxidoreductase
were incubated with 1 µM [14C]progesterone
(Prog) and 0-100 µM troglitazone
(TRO), rosiglitazone (ROSI), and pioglitazone
(PIO). 17 -Hydroxylase activity was assessed as the
conversion rate of [14C]progesterone to
17 -hydroxyprogesterone. B, 17,20-lyase activity.
Microsomes coexpressing P450c17 and OR were incubated with 1 µM [3H]17 -hydroxypregnenolone and 0-100
µM troglitazone, rosiglitazone, or pioglitazone.
17,20-Lyase activity was assessed as the conversion rate of 17-Preg to
DHEA. C, 3 HSDII activity. Microsomes prepared from yeast
expressing human 3 HSDII were incubated with 5 µM
[14C]pregnenolone (Preg) and 0-100
µM troglitazone, rosiglitazone, or pioglitazone.
3 HSDII activity was assessed as the conversion rate of
[14C]pregnenolone to progesterone (Prog). Each
data point represents the mean ± S.D. of triplicate
determinations.
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 |
DISCUSSION |
Insulin-sensitizing drugs increase insulin sensitivity and
decrease hyperandrogenemia in women with PCOS (11-14), and it has been
suggested that metformin decreases P450c17 activity in PCOS (12, 31,
32), but this suggestion has been based on serum hormone values rather
than on direct biochemical study. In our microsomal system we found no
evidence for a direct inhibition of P450c17 or 3
HSDII by metformin,
even in concentrations far exceeding the usual therapeutic
concentrations of 10-20 µM (33). Thus the inhibitory
effect of metformin on androgen synthesis seems to be mediated only
indirectly, most likely by lowering circulating insulin concentrations.
Similarly, lowering insulin concentrations without drug treatment, by
dieting and weight loss, decreases circulating androgen concentrations
in women with PCOS (31, 34, 35).
However, we have now shown that troglitazone, in contrast to metformin,
exerts a direct inhibitory effect on the enzymatic activities of
P450c17 and 3
HSDII, thus directly interfering with androgen
biosynthesis. This effect probably contributes to the androgen-lowering
effect of troglitazone observed in women with PCOS because enzymatic
inhibition occurs at pharmacologically relevant concentrations.
Therapeutic concentrations of troglitazone in serum are 2-10
µM (36). If the intracellular concentrations are
equivalent, 2-10 µM troglitazone would inhibit 20-50%
of P450c17 activity and 5-20% of 3
HSDII activity. Although
intracellular troglitazone concentrations have not been reported, we
found similar IC50 values in both the microsome assay and
in whole-cell experiments, suggesting that intracellular troglitazone
concentrations may be equivalent to circulating concentrations. Our
kinetic analyses showed that troglitazone exerted competitive
inhibition of P450c17 and a mainly noncompetitive inhibition of
3
HSDII. Thus, the interaction of troglitazone with each enzyme is distinct.
Rosiglitazone and pioglitazone also inhibited P450c17 and 3
HSDII
activities, however, with IC50 values clearly beyond their usual therapeutic serum concentrations of 0.2-1 µM (37,
38). Thus, although the direct inhibition of both P450c17 and 3
HSDII seems to be a general property of thiazolidinedione drugs, only troglitazone does so at concentrations achieved in clinical use. Although the potential actions of rosiglitazone and pioglitazone in
PCOS have not been reported, it is possible that all thiazolidinediones can decrease androgen production by indirect mechanisms involving decreased circulating insulin concentrations.
The observed differential inhibitory effects of thiazolidinedione drugs
on the key androgen biosynthetic enzymes P450c17 and 3
HSDII do not
correlate with their differential binding affinity to PPAR
.
Troglitazone shows the weakest binding to PPAR
and is only a partial
agonist, whereas rosiglitazone and pioglitazone bind to PPAR
with
much higher affinity and concurrently exhibit more potent
insulin-sensitizing effects (39-42). Thus, distinct and different
regions of the thiazolidinedione drugs might be involved in PPAR
binding and inhibition of P450c17 and 3
HSDII, respectively. Further
understanding of structure-function relationships in thiazolidinedione
drugs may facilitate more specific drug design, aiming at inhibitory
effects on steroidogenesis as well as at more potent
insulin-sensitizing effects.
 |
ACKNOWLEDGEMENTS |
We thank Drs. John W. M. Martens and
Amit V. Pandey for helpful discussions and Dr. Wolfgang Jacobson for
assistance with the liquid chromatography/mass spectrometry analysis.
 |
FOOTNOTES |
*
This work was supported by National Cooperative Program for
Infertility Research Grant U54-HD 34449 (to W. L. M.), National Institutes of Health Grants K08-DK 02387 (to R. J. A.) and R01-DK 37922 (to W. L. M.), and research fellowship Grant Ar 310/2-1 from
the Deutsche Forschungsgemeinschaft (to W. A.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
¶
To whom correspondence should be addressed: Dept. of
Pediatrics, Bldg. MR-IV, Rm. 209, University of California, San
Francisco, CA 94143-0978. Tel.: 415-476-2598; Fax: 415-476-6286;
E-mail: wlmlab@itsa.ucsf.edu.
Published, JBC Papers in Press, February 7, 2001, DOI 10.1074/jbc.M100040200
 |
ABBREVIATIONS |
The abbreviations used are:
17-Preg, 17
-hydroxypregnenolone;
DHEA, dehydroepiandrosterone;
3
HSDII, 3
-hydroxysteroid dehydrogenase type II;
17OHP, 17
-hydroxyprogesterone;
PCOS, polycystic ovary syndrome;
PPAR
, peroxisome proliferator-activated receptor
;
OR, oxidoreductase.
 |
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