Page 349 - The Toxicology of Fishes

Liver Toxicity 329

reach this organ. The liver has a dual blood supply. Arterial blood reaches the liver by way of the
hepatic artery, a branch of the celiacomesenteric artery from the dorsal aorta. An afferent venous
supply, the hepatic portal vein, is the major source of blood to the liver. Whether the source is arterial
or venous, blood from both sources enters the capillary bed, hepatic sinusoids, or microvasculature
of the liver. In turn, this bed of capillary-like vessels, the hepatic sinusoids, is the basis for the liver
being referred to as a richly perfused compartment, one especially equipped with special modifications
of the endothelial cells (i.e., fenestrae and an absence of basement membrane) that facilitate rapid
uptake of substances. The exit path for hepatic blood is also of great importance, as the release of
toxic substances such as acute-phase proteins following liver injury may affect the structure and
function of downstream organs (heart, gill, brain). Venous flow from the liver is described later in
this chapter.
Due to the dual blood supply of the liver, it is important for us to consider two principal routes of
uptake that may lead to hepatic distribution of potentially toxic compounds. These are the intestinal
uptake route and the branchial one. For important information in this regard, the reader is referred to
two other chapters in this text, Chapter 8 and Chapter 3.
For those compounds with log K values of 3 to 4, accumulation by fish is primarily by the
ow
aqueous route (McKim and Nichols, 1994), and much of this will involve the gill. These compounds
may first interact with the surficial branchial and branchial endothelial cells. From here the compounds
may take a more direct route to the liver but one that requires passage into the dorsal aorta and its
branches, as described above, before it reaches the liver. For that portion of branchial blood that goes
directly to the head or is distributed to organs, such as the swim bladder, an indirect path involving
venous return of compounds back to the heart and another pass through the branchial circulation
before entry in liver are used. Clearly, the liver is not an initial or primary target for compounds
taken up by tissues such as the gills (Barron et al., 1989) but may be exposed to a combination of
parent compound and metabolites from more proximate cells and tissues. With the swallowing of
water, the gut becomes a possible route for the uptake of polar compounds. With this route, the liver
is a more direct target, but metabolism within the wall of the intestine (Van Veld et al., 1997) is
likely prior to entry in liver.
For those compounds with log K > 6, uptake will likely be by the dietary route. This includes
ow
polychlorinated biphenyls (PCBs), dioxins, dichlorodiphenyltrichloroethane (DDT) and its metabolites,
and other persistent organic pollutants (POPs). For the sake of liver toxicity, important questions include:
How much and what type of metabolism occurs prior to entry in liver? On a volume basis, the liver
receives the vast majority of its blood supply by way of the hepatic portal vein. This strategic location
means that capillary beds within the walls of the stomach (gastric fishes), the entire intestinal tract, and
the spleen are tributaries to the hepatic portal vein. The liver is therefore an early but not the first organ to
encounter ingested nutrients, vitamins, metals, drugs, and environmental toxicants, as well as waste products
of bacteria that enter hepatic portal blood. At the present, we lack information on first-pass metabolism
in the wall of the alimentary canal and in the spleen; however, ample evidence from studies with toadfish
(Opsanus tau), spot (Leiostomus xanthurus), channel catfish (Ictalurus punctatus), mummichog (Fun-
dulus heteroclitus), and tilapia (Oreochromis mossambicus) suggests that the intestine, and not the liver,
is the initial metabolic organ following dietary exposure to polycyclic aromatic hydrocarbons (PAHs)
and halogenated hydrocarbons (James and Kleinow 1994; James et al., 1996, 1997; Kleinow et al., 1998;
Van Veld et al., 1987, 1988; Vetter et al., 1985; Yeung et al., 2003). How much of the compound is
sequestered in other organs prior to the liver? We are not aware of studies that have shown a differential
hepatic toxicity in relation to the uptake route. At the present time, it is difficult to make a reasonable
prediction on the relevance of specific uptake routes for liver toxicity.
Finally, the skin may represent an important route for uptake, particularly for the early life stages of
fish. From the skin, venous return to the sinus venosus, passage through the heart, and return through
the branchial circulation (to a varying degree dependent on development) would be necessary before
the compounds would reach the liver. Given the strategic location of the liver, however, its complement
of enzymes, its dual blood supply, and the enterohepatic circulation, this organ is a major target for
xenobiotics whatever the exposure route considered.