Page 379 - The Toxicology of Fishes

Liver Toxicity 359

behavior, and physiological function of NRs is of particular interest given their diverse role in coordi-
nating numerous biological processes. The origins of nuclear receptor interactions are unknown, yet
NRs have been found in almost all animal species examined thus far. NRs play a significant role in the
liver physiology of all animals, including the uptake, metabolism, storage, and redistribution of nutrients
and endogenous molecules, metabolism of xenobiotics, and formation and excretion of bile. Studies in
teleosts to date suggest that there are substantial differences in the structure and possibly functions of
teleost NRs. Because fish stand between invertebrates and higher vertebrates in evolution, they may
serve as unique models for the study of the evolutionary and physiological significance of NRs. From
a toxicological perspective, we have yet to determine if these NRs are true targets for exogenous
compounds and xenobiotics as described for mammalian species. With PXR, numerous species-specific
ligand-binding profiles exist, but the molecular and physiological functions of teleost NRs have yet to
be determined. As we continue to explore the molecular dynamics of teleost nuclear hormone receptors
and analyze ligand-specific interactions, DNA-binding characteristics, and comodulator recruitment, we
will gain new insights into the evolution of NR-mediated transcription regulation and the importance of
receptor subfunctionaliztion and will broaden our understanding of the role of NRs in governing liver-
specific processes in lower vertebrates.

Introduction to Bile Synthesis and Transport
Bile acid synthesis and secretion, performed by hepatocytes and biliary epithelial cells, are vital for the
assimilation of lipid-soluble dietary nutrients (e.g., vitamins A, K, and E; triacylglycerols) and the
elimination of endogenous metabolic byproducts and wastes (e.g., bilirubin, hormones). Equally impor-
tant is the role of bile in the elimination of xenobiotics (environmental toxicants, carcinogens, drugs,
and their metabolites). The physiological importance of these processes renders bile synthesis and
secretion critical life functions.
The hepatobiliary transport of substances (e.g., bile salts, inorganic and organic solutes) from blood
to bile includes three major steps. First, uptake of substances from blood plasma across the sinusoidal
membrane and then into the hepatocytes must occur. This in turn is followed by intracellular transport
and metabolism. Finally, transport of the parent substances or metabolites occurs across the apical
membrane of hepatocytes into biliary passageways (Groothuis and Meijer, 1996; Nathanson and Boyer,
1991).
As a brief review of the biliary passageways in liver, the terminal branches of the intrahepatic biliary
system are canaliculi, microscopic passageways 1 to 2 mm in diameter, that are formed by, and between,
adjacent hepatocyte membranes and delineated by tight junctions. Next are transitional zones in which
bile preductular epithelial cells (cells with high nuclear-to-cytoplasmic ratios) form junctional complexes
with hepatocytes, at which are created bile preductules. Bile preductules provide for movement of bile
from canaliculi to bile ductules (cholangioles). The walls of the latter are completely comprised of biliary
epithelial cells. From here, bile passes through a network of ductules that feed larger intrahepatic bile
ducts as the bile moves toward the liver hilus. From the hilus, bile is conducted to the extrahepatic biliary
system. The latter is comprised of one or more hepatic ducts that conduct bile into the bile duct. From
this structure, a cystic duct arises that conducts bile to and from the gallbladder. From the point between
the cystic duct and the intestinal wall, the passageway is known as the common bile duct. All of these
components are discussed in the section on cells of the teleost liver.
Because pressures within bile spaces exceed those of the sinusoids, hydrostatic forces alone cannot
account for bile flow (Trauner and Boyer, 2003). Flow of bile from sinusoids to canaliculi (blood to bile
transport), through the hepatocyte, is a secretory and concentrative process driven by a suite of trans-
membrane transporters (discussed later in this chapter); for example, in rodents blood to bile transport
is uphill against a 100- to 1000-fold concentration gradient. Bile flow in the intrahepatic biliary system
is also regulated by the contraction of canaliculi, the functional aspects of which are mechanically
governed by cytoskeletal elements in the pericanalicular cytoplasm. Because cytoskeletal proteins are
key regulators of proper canalicular development and function, impairment of cytoskeletal function by
endogenous or exogenous compounds is a key mechanism by which altered bile transport (toxicity)