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

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Chapter | 13 Hepatic Function
20
Serum Bilirubin (mg/dl)
15
10
5
FIGURE 13-8 Total serum bilirubin concentrations of 23 normal Shetland
ponies (upper; 143 observations) and 103 normal standard-sized horses
(lower; 345 observations). Note the higher median values of standardsized
horses and the wide range of values in clinically healthy adults.
C . Serum Bile Acids
4 5 2 3
Feline Ovine Canine Equine
FIGURE 13-7 Comparative changes in total and conjugated ( “direct
reacting ” ) serum bilirubin 14 days following complete experimental bile
duct obstruction in cats, sheep, dogs, and horses Shaded portion of bar:
direct reacting; bar eight: total. Courtesy of Dr. D. Levy.
Synthesis of the primary bile acids is the principal pathway
for catabolism of cholesterol. Multiple enzymatic
FIGURE 13-9 Serum bilirubin of horses before, during, and following
a 3-day period of total fasting.
steps are required for hepatic synthesis of the primary
bile acids of most species, cholic acid and, chenodeoxycholic
acid ( Fig. 13-10 ). In swine, hyocholic acid is
derived in the liver from chenodeoxycholic acid and is
the major primary bile acid of swine. The classic pathway
of bile acid synthesis is initiated by the liver-specific
enzyme, cholesterol 7 α -hydroxylase (CYP7A1), which
converts cholesterol to 7 α -hyroxycholesterol. This is the
initial, rate-limiting step in the synthesis of cholic acid.
Alternate pathways are recognized that are initiated by
(1) sterol 27-hydroxylase (CYP27), an enzyme expressed
in the liver and in multiple other tissues; (2) cholesterol
25-hydroxylase that is present in the heart, lung, and kidney;
or (3) cholesterol 24-hydroxylase (CYP46) that is
present primarily in the brain. Oxysterols produced by these
three enzymes are transported by the circulation to the liver
where 25- and 27-hydroxycholesterol are hydroxylated
further by an oxysterol 7 α -hydroxylase (CYP7B1) and
where 24-hydroxycholesterol is hydroxylated by another
7 α -hydroxylase (CYP39A1). The 7 α steroids produced
by the alternate pathways are preferentially utilized as precursors
of chenodeoxycholic acid ( Beigneux et al., 2002 ).
In knockout mice in which the CYP7A1 gene is missing
(CYP7A1[-/-]), CYP7A1 activity was not detectable, but
total oxysterol 7α-hydroxylase activity in CYP7A1(-/-)
mice was similar to that of controls. Bile acid synthesis
in CYP7A1(-/-) mice was remarkably reduced and total
bile acid secretion was diminished. Because oxysterol
7α-hydroxylase activity was not elevated in CYP7A1(-/-)
mice, the results suggested that in normal mice the alternate
pathway may account for as much as 40% of total bile
acid synthesis ( Schwarz et al., 1998 ).
Following synthesis, primary bile acids are conjugated
either with taurine or glycine and transported across the
bile canalicular membrane primarily by the bile salt export