Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 19 Adrenocortical Function
FIGURE 19-1 Numbers of the carbon atoms and letters designating the
rings of the pregnenolone molecule ( IUPAC-IUB, 1989 ).
In birds aldosterone and corticosterone are the main
corticosteroids secreted. Zonation of the avian adrenal is
less clear than in the mammalian adrenal. However, the
outer subcapsular cells, looping in a manner similar to the
zona glomerulosa, appear to be the predominant aldosterone
secretors. The cells reaching toward the central part
of the gland form corticosterone ( Kime, 1987 ).
A . Steroid Nomenclature
The adrenal steroids contain as their basic structure a
cyclopentanoperhydrophenanthrene nucleus consisting
of three six-carbon rings (A, B, and C) and a single fivecarbon
ring (D). The letter designations for the carbon
rings, and the numbers of the carbon atoms are shown for
pregnenolone ( Fig. 19-1 ), a key biosynthetic intermediate.
The Greek letter Δ indicates a double bond, as does the
suffix -ene. The position of a substituent below or above the
plane of the steroid ring is indicated by α and β , respectively.
The α substituent is drawn with a broken line (e.g.--OH)
and the β substituent with a solid line (e.g.-OH).
The C 18 steroids, which are devoid of a side chain at C-
17 and have a substituent at C-18, are estrogens. The C 19
steroids, which have substituent methyl groups at positions
C-18 and C-19, are androgens (see also Fig. 19-1 )
(IUPAC-IUB, 1989 ).
Steroids that have a ketone group at C-17 are termed
17-ketosteroids. The C 21 steroids, the corticosteroids and
progestagens, are those that have a two-carbon side chain
(C-20 and C-21) attached at C-17 and in addition have
substituent methyl groups at C-18 and C-19. The C 21 steroids
that also possess a hydroxyl group at position 17 are
termed 17-hydroxy-corticosteroids and may have predominantly
glucocorticoid properties.
B . Biosynthesis
Cholesterol, derived from food and from endogenous
synthesis via acetate ( Fig. 19-2 ), is the principal starting
compound in steroidogenesis. The adrenal gland is
enriched in receptors that internalize low- and high-density
lipoproteins. This uptake mechanism increases when the
adrenal is stimulated and provides the major cholesterol
source. Subsequent steps occur in the mitochondrion or
at the endoplasmic reticulum. Two classes of enzymes
are involved in the synthesis of steroids, the cytochrome
P450 (CYP) heme-containing proteins that catalyze mainly
hydroxylation reactions and the hydroxysteroid dehydrogenases
(HSD) that are involved in oxidation and reduction
reactions ( Payne and Hales, 2004 ). The human CYP
enzymes are written with capitals, whereas in mice lowercase
is used. For other species no rules are given, but we
will use here the abbreviations as used for human.
The precursor cholesterol has a side chain that is cleaved
by CYP11A1 resulting in formation of pregnenolone ( Fig.
19-2 ). Mice defective in the Cyp11a1 gene produce no steroids,
survive during embryogenesis, but die after birth ( Hsu
et al ., 2006 ). The zonal difference in adrenocortical hormone
production is due to two steroidogenic enzymes. The mitochondrial
CYP11B2 (aldosterone synthase), which converts
11-deoxycorticosterone by 11 β -hydroxylation and the formation
of a carbon 18 aldehyde group toward aldosterone,
is found only in the zona glomerulosa. The characteristic
enzymes of the inner zones are the microsomal CYP17 (17 α -
hydroxylase/17,20 lyase) and the mitochondrial CYP11B1
(11 β -hydroxylase). CYP17 catalyzes the 17 α-hydroxylation
of pregnenolone and progesterone as well as the side chain
fission of 17 α -hydroxy C21 steroids resulting in the formation
of dehydroepiandrosterone (DHEA) or androstenedione
( Fig. 19-2 ). CYP11B1 catalyzes the 11 β -hydroxylation in the
zona fasciculata and reticularis ( Payne and Hales, 2004 ). The
other steroidogenic enzymes are present in all three zones of
the adrenal cortex ( Müller, 1986 ).
In rat, mouse, guinea pig, baboon, and hamster two
distinct CYP11B forms are found, in contrast with cow,
pig, sheep, and frogs where the formation of glucocorticoids
and mineralocorticoids is catalyzed by a single 11 β -
hydroxylase (CYP11B1) ( Lisurek and Bernhardt, 2004 ).
The characteristic microsomal 21-hydroxylating
(CYP21) and mitochondrial 11 β-hydroxylating (CYP11B1)
enzymes appear to have developed at an early stage of
evolution and are present in all vertebrates. Also, the
18-oxygenated corticosteroids (CYP11B2) retain their
importance as mineralocorticoids in all vertebrates. For the
17 α hydroxylation (CYP17) potential, the situation is different.
Most mammals secrete cortisol as the predominant
glucocorticoid. However, rodents and birds secrete predominantly
17-deoxycorticosteroids such as corticosterone.
In line with this, steroid determinations in adrenal venous
blood of dogs ( Hirose et al ., 1977 ) have revealed cortisol/