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

IV. Laboratory Assessment of Hepatic Function
399
LIVER
ILEUM
LARGE INTESTINE
PRIMARY
BILE ACIDS
O
C
OH
HO OH
CHENODEOXYCHOLIC ACID
O
C
OH
CONJUGATION
GLYCO-, TAURO–
CHENODEOXYCHOLIC
SECONDARY
BILE ACIDS
Bacteria
O
C
OH
HO
LITHOCHOLIC ACID
Feces
HO
CHOLESTEROL
OH
HO OH
CHOLIC ACID
O
C
OH
GLYCO-, TAURO–
TAUROCHOLIC
DEOXYCHOLIC ACID
OH
O
Bacteria
C
OH
HO
Enterohepatic
Circulation
FIGURE 13-10 Metabolism of bile acids in the liver and intestinal tract. The primary bile acids are formed in
the liver and the secondary bile acids in the large intestine.
pump (BSEP, Sister of P-glycoprotein [Spgp], ABCB11)
a multidrug resistance P-glycoprotein that belongs to the
ATP-binding cassette (ABC) superfamily of transport proteins.
The sodium and ATP-mediated BSEP carrier determines
the bile salt dependent fraction of canalicular bile
flow. The important bile salt independent fraction of bile
flow is determined by canalicular MrP2 which is responsible
for transport of glutahione, glutathione conjugates, and
conjugates of glucuronic acid including bilirubin glucuronide.
In the dog, horse, and sheep, taurine conjugates of bile
acids predominate, and in the cat, bile acids are conjugated
exclusively with taurine. In cattle, the bile is rich in taurine
conjugated bile acids and contains glycine conjugates of
chenodeoxycholate and deoxycholate ( Haslewood, 1967 ).
Bile acids are transported from the canaliculus through bile
ducts to the lumen of the duodenum. In the duodenum and
jejunum, bile acids have an important role in the digestion
and absorption of dietary fat and other lipids including fatsoluble
vitamins.
In the terminal ileum, almost all of the bile acids
secreted by the liver are absorbed by highly efficient
transport mechanisms of the ileal epithelium and enter
the hepatic portal vein (the enterohepatic circulation; see
Chapter 14) . Normally, only a small fraction (5%) of the
bile acids that enter the duodenum reach the large intestine
where bacteria are responsible for deconjugation and for
the formation of secondary bile acids by dehydroxylation.
Dehydroxylation of cholic acid at the 7 α position results in
formation of deoxycholic acid, and 7 α dehydroxylation of
chenodeoxycholic acid results in production of lithocholic
acid. The secondary bile acids formed in the large intestine
may be absorbed and return to the liver by the enterohepatic
circulation or excreted in the feces.
Taurocholate is the major bile acid of mice and rats.
These species have the unique capacity to rehydroxylate
deoxycholate at the C-7α position in the liver to reform
cholic acid ( Haslewood, 1967 ). The entire bile acid pool
passes from the liver to the intestine and back to the liver
via the enterohepatic circulation several times each day
and under steady state conditions, approximately 5% of the
bile acid pool is lost and replaced by hepatic synthesis.
The primary and secondary bile acids are transported
to the liver via the hepatic portal vein and are transferred
across the sinusoidal (basolateral) cell membrane of the
hepatocyte by the NTCP, which is responsible primarily for
the absorption of conjugated bile acids or by the sodiumindependent
OATP. Following entry, unconjugated bile
acids are conjugated with taurine or glycine, are bound to
cytosolic bile acid binding proteins, and finally are transferred
actively across the bile canaliculus by the BSEP.
Cholestasis may be caused by drugs that inhibit BSEP and
by hereditary defects of BSEP that prevent BSEP expression
and result in severe progressive familial intrahepatic
cholestasis in which the bile contains almost no bile acids
(Alrefai and Gill, 2007) .
The canalicular Mrp2 transporter, which has a primary
role in the excretion of bilirubin conjugates, BSP, and a
wide range of glutathione, glucuronic acid, and sulfate conjugates
(see Section III.A.2) , mediates the canalicular transport
of bile acid conjugates of sulfate or glucuronic acid
but lacks the capacity to transport monovalent bile acids
( Ito et al., 2001 ; Trauner and Boyer, 2003 ). The canaliculus
also contains the multidrug resistance 2 P-glycoprotein
(Mdr2), which is responsible for the transport of cholesterol
and phospholipids into bile. Defects in the Mdr2 gene
product or the absence of Mdr2 in the canaliculus results in