638
16 Sterols and Steroids
the vertebrates are apparently phylogenetically
rather ancient, and the evolution of the vertebrate steroid hormone system began not with the
appearance of the steroid structure but with the
"invention" of specific steroid receptors. It therefore becomes clear why there is no characteristic
structural feature of the vertebrate steroid hormones; even the frequently occurring 3-oxo-4-en
structure (Fig. 16.10) is not universal [39, 74].
The steroid hormones are found in much lower
amounts than the sterols. The human adrenal cortex secretes about 30 mg corticosteroids per day.
However, because of their extremely rapid turnover, the blood plasma contains only about 100 !-lg/1;
the concentration of the sex hormones is one or
two orders of magnitude lower. The extraction of
large quantities of starting material, however, led
to the identification of more than 50 corticosteroids in the blood and over 200 steroids and
steroid metabolites in the urine. Most of these
substances are in fact only intermediates, byproducts or end products of metabolism; the
number of natural hormones is relatively small.
Amongst the corticosteroids of the mammals,
cortisol, cortisone and corticosterone mainly
affect carbohydrate metabolism and are therefore
known as glucocorticoids; aldsterone and 11deoxycorticosterones are the most important
mineral corticoids. Dihydrotestosterone and testosterone are the most typical male sex hormones; the female reproductive process is regulated
mainly by oestradiol, oestrone and progesterone
(for the formulae see Fig. 16.10) [39, 74].
The spectrum of biologically active steroid hormones appears to be similar in all vertebrates,
although the concentrations of individual components may vary. As yet, very few steroid
hormones have been found to be restricted to certain vertebrate groups or species, e.g. equilenin
and equilenin of the horse, or la-hydroxycorticosterone of the elasmobranch. However, it
should be borne in mind that the consistently low
concentrations of the steroid hormones have
resulted in comparative investigations making use
primarily of biological activity or immunological
reactivity, and not physicochemical methods, for
purposes of identification. The variety of steroid
effects in the vertebrates apparently relies more
upon differences in relative concentrations and
reaction chains than on hormone structure. The
primary target of steroid hormone action is gene
transcription in the nucleus. In contrast to the
peptide hormones, the lipophilic nature of the
steroids gives them easy access to the inside of the
cell across the cell membrane. There they are
bound to specific receptors that then interact with
certain regulatory DNA sequences (hormone
regulatory elements) [6]. The same steroid can
have very different effects on different cells or
organisms, depending upon the gene transcribed
and the secondary effect of its product [39, 74].
The steroid receptors belong to the protein
super-family of the nuclear hormone receptors.
They recognize transcriptional enhancer sequences and control networks of genes that have
important effects on growth, development and
homeostasis. They bind specific lipophilic hormones, including not only the steroids but also the
thyroid hormone and retinoic acid. The chicken
ovalbumin upstream promoter transcription factor (COUP-TF) and various receptors of the fly
Drosophila also belong to this super-family
[125, 127]. Despite their functional diversity, the
receptors show extensive agreement in domain
structure and amino acid sequences. Six domains
(A-F) can be distinguished. The DNA-binding
domain C is the most highly conserved in the
super family, and consists of 66-68 amino acids
folded into two zinc-finger motifs. Each finger
binds a zinc ion that is coordinately bound to four
cysteine residues. The first finger determines
DNA-sequence specificity, and the second is
involved in protein-protein interactions, such as
the dimerization of the receptor. The sequence of
the first finger characterizes two subfamilies with
the glucocorticoid and oestrogen receptors as
nominal representatives. The domain E, with
about 250 amino acids, is also well conserved
between members of the super-family; this carries the hormone-binding site and is responsible
for receptor dimerization, nuclear translocation
and hormone-dependent transcriptional activation. An independent transcriptional activation
function is located in domains A and B, the
lengths and sequences of which vary greatly
between the different receptor types. Domain D,
carrying the nuclear localization signal, is also
relatively poorly conserved, as is the C-terminal
domain F. The total length of the nuclear receptors varies between 433 and 934 amino acids.
Additional variation is generated by the existence
of several genes for the same receptor type,
alternative promoters for the same gene, and
alternative splicing [54, 125]. Some steroid receptors appear exclusively in the nuclear fraction on
cell extraction and others appear also in the cytosol. This is apparently due to the low affinity for
chromatin of some receptors. A vertebrate species such as the spiny dogfish, whose tissues have
an extremely high osmolality of 1010 mOsmollkg
16 Sterols and Steroids
the vertebrates are apparently phylogenetically
rather ancient, and the evolution of the vertebrate steroid hormone system began not with the
appearance of the steroid structure but with the
"invention" of specific steroid receptors. It therefore becomes clear why there is no characteristic
structural feature of the vertebrate steroid hormones; even the frequently occurring 3-oxo-4-en
structure (Fig. 16.10) is not universal [39, 74].
The steroid hormones are found in much lower
amounts than the sterols. The human adrenal cortex secretes about 30 mg corticosteroids per day.
However, because of their extremely rapid turnover, the blood plasma contains only about 100 !-lg/1;
the concentration of the sex hormones is one or
two orders of magnitude lower. The extraction of
large quantities of starting material, however, led
to the identification of more than 50 corticosteroids in the blood and over 200 steroids and
steroid metabolites in the urine. Most of these
substances are in fact only intermediates, byproducts or end products of metabolism; the
number of natural hormones is relatively small.
Amongst the corticosteroids of the mammals,
cortisol, cortisone and corticosterone mainly
affect carbohydrate metabolism and are therefore
known as glucocorticoids; aldsterone and 11deoxycorticosterones are the most important
mineral corticoids. Dihydrotestosterone and testosterone are the most typical male sex hormones; the female reproductive process is regulated
mainly by oestradiol, oestrone and progesterone
(for the formulae see Fig. 16.10) [39, 74].
The spectrum of biologically active steroid hormones appears to be similar in all vertebrates,
although the concentrations of individual components may vary. As yet, very few steroid
hormones have been found to be restricted to certain vertebrate groups or species, e.g. equilenin
and equilenin of the horse, or la-hydroxycorticosterone of the elasmobranch. However, it
should be borne in mind that the consistently low
concentrations of the steroid hormones have
resulted in comparative investigations making use
primarily of biological activity or immunological
reactivity, and not physicochemical methods, for
purposes of identification. The variety of steroid
effects in the vertebrates apparently relies more
upon differences in relative concentrations and
reaction chains than on hormone structure. The
primary target of steroid hormone action is gene
transcription in the nucleus. In contrast to the
peptide hormones, the lipophilic nature of the
steroids gives them easy access to the inside of the
cell across the cell membrane. There they are
bound to specific receptors that then interact with
certain regulatory DNA sequences (hormone
regulatory elements) [6]. The same steroid can
have very different effects on different cells or
organisms, depending upon the gene transcribed
and the secondary effect of its product [39, 74].
The steroid receptors belong to the protein
super-family of the nuclear hormone receptors.
They recognize transcriptional enhancer sequences and control networks of genes that have
important effects on growth, development and
homeostasis. They bind specific lipophilic hormones, including not only the steroids but also the
thyroid hormone and retinoic acid. The chicken
ovalbumin upstream promoter transcription factor (COUP-TF) and various receptors of the fly
Drosophila also belong to this super-family
[125, 127]. Despite their functional diversity, the
receptors show extensive agreement in domain
structure and amino acid sequences. Six domains
(A-F) can be distinguished. The DNA-binding
domain C is the most highly conserved in the
super family, and consists of 66-68 amino acids
folded into two zinc-finger motifs. Each finger
binds a zinc ion that is coordinately bound to four
cysteine residues. The first finger determines
DNA-sequence specificity, and the second is
involved in protein-protein interactions, such as
the dimerization of the receptor. The sequence of
the first finger characterizes two subfamilies with
the glucocorticoid and oestrogen receptors as
nominal representatives. The domain E, with
about 250 amino acids, is also well conserved
between members of the super-family; this carries the hormone-binding site and is responsible
for receptor dimerization, nuclear translocation
and hormone-dependent transcriptional activation. An independent transcriptional activation
function is located in domains A and B, the
lengths and sequences of which vary greatly
between the different receptor types. Domain D,
carrying the nuclear localization signal, is also
relatively poorly conserved, as is the C-terminal
domain F. The total length of the nuclear receptors varies between 433 and 934 amino acids.
Additional variation is generated by the existence
of several genes for the same receptor type,
alternative promoters for the same gene, and
alternative splicing [54, 125]. Some steroid receptors appear exclusively in the nuclear fraction on
cell extraction and others appear also in the cytosol. This is apparently due to the low affinity for
chromatin of some receptors. A vertebrate species such as the spiny dogfish, whose tissues have
an extremely high osmolality of 1010 mOsmollkg