648
16 Sterols and Steroids
sorbed and recycled into bile (entero-hepatic circulation), about 20-30 g bile acids are released
into the gut each day. The bile acids may be chemically modified by gut bacteria during their residence in the gut lumen, and may be further metabolized in the liver after resorption. The metabolites produced by this combination of bacterial
and animal metabolism are referred to as secondary bile acids. For example, the deoxycholic acid
which is commonly found in higher vertebrates
arises from the cleavage by gut bacteria of the 7ahydroxyl group of cholic acid [46].
The biosynthesis of various bile acids and bile
alcohols from cholesterol has been demonstrated
by tracer experiments for all classes of vertebrates. The synthesis of cholic acid from cholesterol
initially requires the introduction of hydroxyl
groups into the 7a and 12a positions, the epimerization of the 3~-OH to 3a-OH, and the reduction of the /).5 double bond. The intermediates
formed are 7a-hydroxy-4-cholesten-3-one and 5~cholestan-3a,7a,12a-triol. Finally, a part of the
side-chain on C-24 is cleaved off as propionylCoA (Fig. 16.17). The biosynthesis of the bile
alcohol Sa-cyprinol proceeds analogously via Sacholestan-3a,7a,12a-triol. The numerous tracer
experiments on vertebrates of all classes and
involving different precursors or intermediates
have resulted in a confusing picture of the metabolism of bile salts; the same product can apparently be produced via different pathways from the
same precursor, but the same precursor also
yields different products depending upon the species and the physiological condition of the experimental animal. A multitude of species-specific
differences is even found in the metabolism of the
bile alcohols and bile acids, and this is probably
based upon differences in enzyme complement.
For example, some amphibians and all crocodiles
lack the ability to shorten the cholesterol sidechain, and certain hydroxylations are restricted to
individual groups or species [2S, 46]. The enzymes involved in the biosynthesis of bile salts have
also been only partly described in the mammals,
and there are almost no comparative data. The
7a- and 12a-hydroxylases are microsomal cytochrome P-4S0 enzymes, but the 27-hydroxylase
is located in the mitochondria [lS]. Prior to conjugation, bile acids must be activated by the bile
acid: CoA ligase. This is the rate-limiting step of
bile acid conjugation. The ligase isolated from the
liver of the codfish Ophiodon elongatus has a
much lower affinity than the mammalian enzyme
and is present in lower amounts [122]. The bile
acid-CoA : taurine/glycine acyltransferases from
the chicken and bovine liver have been isolated.
The taurine-specific enzyme of the chicken has a
mass of 47-51 kDa and is significantly shorter
than the glycine/taurine-specific bovine enzyme
of 63-6S kDa. It may be that the ability of the
bovine enzyme to bind glycine as well as taurine
is related to the extension of the polypeptide
chain by about 12S amino acids. The transferases
from non-mammals are highly specific for taurine. The liver enzyme of the teleost Ophiodon
metabolizes glycine with a 100-fold lower efficiency than taurine. This teleost liver enzyme is a
dimer of 100 kDa, whereas the enzymes from
mammals and birds are monomers of SO and
60 kDa, respectively [122].
16.5.2 Bile Salts of Individual Animal
Groupsl
The gall bladders of agnathans in the genera Myxine and Eptatretus, which are considered to be the
most primitive vertebrates, mainly contain myxinol bissulphate. This is also the most primitive
bile alcohol that still includes the complete cholesterol basic element (Sa-cholestan) and a 3~hydroxyl; it is the only double sulphated bile alcohol and is much less effective as a detergent than
any other bile alcohol. The predominant bile salt
of the higher agnathan Petromyzon marinus is
Sa-petromyzonol sulphate; this is much more
developed and has a shortened side-chain and a
3a-hydroxyl group. The cartilaginous fish also
contain unique bile salts; the Sj3-chimaerol z from
Chimaera monstruosa differs from the scymnol,
which is common in sharks and rays, by the
absence of the 27-0H. Cholic acid is also produced from radio labelled cholesterol in the dogfish Scyliorhinus canicula but is normally present
only in trace amounts [46, 61]. The latimerol
found in the crossopterygian Latimeria chalumnae, one of the oldest bony fish, has a primitive
3~-hydroxyl group and appears to be the evolutionary precursor of Sa-cyprinol. In fact, in addition to latimerol, the crossopterygians have the
related 5a-cholestan-3~, 7a,12a,2S,26-pentol and
Sa-cyprinol, as well as traces of different CZ7, Cz6
and even Cz4 bile acids [62].
1 The structures of all the bile alcohols and bile acids
mentioned in the text are given in Fig. 16.16.
2 As for all bile alcohols, these are also found in the gall
bladder as sulphate esters; for the sake of brevity, "sulphate" is omitted from the names of the bile alcohols in the
following text.
16 Sterols and Steroids
sorbed and recycled into bile (entero-hepatic circulation), about 20-30 g bile acids are released
into the gut each day. The bile acids may be chemically modified by gut bacteria during their residence in the gut lumen, and may be further metabolized in the liver after resorption. The metabolites produced by this combination of bacterial
and animal metabolism are referred to as secondary bile acids. For example, the deoxycholic acid
which is commonly found in higher vertebrates
arises from the cleavage by gut bacteria of the 7ahydroxyl group of cholic acid [46].
The biosynthesis of various bile acids and bile
alcohols from cholesterol has been demonstrated
by tracer experiments for all classes of vertebrates. The synthesis of cholic acid from cholesterol
initially requires the introduction of hydroxyl
groups into the 7a and 12a positions, the epimerization of the 3~-OH to 3a-OH, and the reduction of the /).5 double bond. The intermediates
formed are 7a-hydroxy-4-cholesten-3-one and 5~cholestan-3a,7a,12a-triol. Finally, a part of the
side-chain on C-24 is cleaved off as propionylCoA (Fig. 16.17). The biosynthesis of the bile
alcohol Sa-cyprinol proceeds analogously via Sacholestan-3a,7a,12a-triol. The numerous tracer
experiments on vertebrates of all classes and
involving different precursors or intermediates
have resulted in a confusing picture of the metabolism of bile salts; the same product can apparently be produced via different pathways from the
same precursor, but the same precursor also
yields different products depending upon the species and the physiological condition of the experimental animal. A multitude of species-specific
differences is even found in the metabolism of the
bile alcohols and bile acids, and this is probably
based upon differences in enzyme complement.
For example, some amphibians and all crocodiles
lack the ability to shorten the cholesterol sidechain, and certain hydroxylations are restricted to
individual groups or species [2S, 46]. The enzymes involved in the biosynthesis of bile salts have
also been only partly described in the mammals,
and there are almost no comparative data. The
7a- and 12a-hydroxylases are microsomal cytochrome P-4S0 enzymes, but the 27-hydroxylase
is located in the mitochondria [lS]. Prior to conjugation, bile acids must be activated by the bile
acid: CoA ligase. This is the rate-limiting step of
bile acid conjugation. The ligase isolated from the
liver of the codfish Ophiodon elongatus has a
much lower affinity than the mammalian enzyme
and is present in lower amounts [122]. The bile
acid-CoA : taurine/glycine acyltransferases from
the chicken and bovine liver have been isolated.
The taurine-specific enzyme of the chicken has a
mass of 47-51 kDa and is significantly shorter
than the glycine/taurine-specific bovine enzyme
of 63-6S kDa. It may be that the ability of the
bovine enzyme to bind glycine as well as taurine
is related to the extension of the polypeptide
chain by about 12S amino acids. The transferases
from non-mammals are highly specific for taurine. The liver enzyme of the teleost Ophiodon
metabolizes glycine with a 100-fold lower efficiency than taurine. This teleost liver enzyme is a
dimer of 100 kDa, whereas the enzymes from
mammals and birds are monomers of SO and
60 kDa, respectively [122].
16.5.2 Bile Salts of Individual Animal
Groupsl
The gall bladders of agnathans in the genera Myxine and Eptatretus, which are considered to be the
most primitive vertebrates, mainly contain myxinol bissulphate. This is also the most primitive
bile alcohol that still includes the complete cholesterol basic element (Sa-cholestan) and a 3~hydroxyl; it is the only double sulphated bile alcohol and is much less effective as a detergent than
any other bile alcohol. The predominant bile salt
of the higher agnathan Petromyzon marinus is
Sa-petromyzonol sulphate; this is much more
developed and has a shortened side-chain and a
3a-hydroxyl group. The cartilaginous fish also
contain unique bile salts; the Sj3-chimaerol z from
Chimaera monstruosa differs from the scymnol,
which is common in sharks and rays, by the
absence of the 27-0H. Cholic acid is also produced from radio labelled cholesterol in the dogfish Scyliorhinus canicula but is normally present
only in trace amounts [46, 61]. The latimerol
found in the crossopterygian Latimeria chalumnae, one of the oldest bony fish, has a primitive
3~-hydroxyl group and appears to be the evolutionary precursor of Sa-cyprinol. In fact, in addition to latimerol, the crossopterygians have the
related 5a-cholestan-3~, 7a,12a,2S,26-pentol and
Sa-cyprinol, as well as traces of different CZ7, Cz6
and even Cz4 bile acids [62].
1 The structures of all the bile alcohols and bile acids
mentioned in the text are given in Fig. 16.16.
2 As for all bile alcohols, these are also found in the gall
bladder as sulphate esters; for the sake of brevity, "sulphate" is omitted from the names of the bile alcohols in the
following text.