DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1196
21
H 3 C 20
H 3 C
17
11
CH 3
side chain
cleavage
HO
3
1
cellular
cholesterol
CH 3
CH 3
H 3 C
acetate
plasma cholesterol
SECTION V
HORMONES AND HORMONE ANTAGONISTS
3β-hydroxysteroid
dehydrogenase
pregnenolone
pregesterone
17α-hydroxylase
17α OH-pregnenolone
17α OH-progesterone
to be mediated by testosterone itself, some by dihydrotestosterone,
and some by estradiol.
The enzyme 5α-reductase catalyzes the conversion
of testosterone to dihydrotestosterone. Although
both testosterone and dihydrotestosterone act via the
androgen receptor, dihydrotestosterone binds with
higher affinity (Wilbert et al., 1983) and activates gene
expression more efficiently (Deslypere et al., 1992). As
17, 20 lyase
dehydroepiandrosterone
(DHEA)
androstenedione
O
H 3 C
androstenediol
testosterone
Figure 41–1. Pathway of synthesis of testosterone in the Leydig cells of the testes. In Leydig cells, the 11 and 21 hydroxylases (present
in adrenal cortex) are absent but CYP17 (17 α-hydroxylase) is present. Thus androgens and estrogens are synthesized; corticosterone
and cortisol are not formed. Bold arrows indicate favored pathways.
OH
a result, acting via dihydrotestosterone and in tissues
expressing 5α-reductase, testosterone is able to affect
tissues that would otherwise not be affected by circulating
levels of testosterone. Two forms of 5α-reductase
Active
Metabolites
DIHYDROTESTOSTERONE
OH
Inactive
Metabolites
ANDROSTERONE
O
SERUM TESTOSTERONE, ng/dl
500
250
Gestation
Infancy
Puberty
Adulthood
O
H
Childhood
5αreductase
O
A
3
4
CYP19
OH
19
5
C
B
18 OH
17
D
(aromatase)
HO
H
TESTOSTERONE
O
0
1 10 20 100
AGE (years)
Figure 41–2. Schematic representation of the serum testosterone
concentration from early gestation to old age.
HO
ESTRADIOL
HO
H
ETIOCHOLANOLONE
Figure 41–3. Metabolism of testosterone to its major active and
inactive metabolites.