Page 83 - The Toxicology of Fishes

Toxicokinetics in Fishes 63

along the substrate concentration continuum competition for reaction sites results in a maximal rate of
metabolism or transport. Under these conditions, the rate of metabolism or transport becomes independent
of substrate concentration and is said to exhibit zero-order kinetics. Saturation of capacity-limited systems
can result in profound effects on xenobiotic distribution and disposition.

Carrier-Mediated Transport
Carrier-mediated membrane transport occurs by rapidly reversible interactions between components of
the membrane and the transported substance. These carriers generally exhibit selectivity for chemicals
that possess specific characteristics; however, multiple chemicals possessing these characteristics may
compete for the carrier. Saturability and competitive inhibition are characteristic of carrier-mediated
transport. Active transport is a transmembrane carrier-mediated process that requires the direct expen-
diture of energy. The biological energy source may exist in several forms, including the nucleoside
adenosine triphosphate (ATP) or as a transmembrane ion gradient. Of the latter, sodium gradients are
most common. Active transport mechanisms are widely found in aquatic species and support a variety
of physiological processes; for example, amino acids and carbohydrates are actively absorbed in the
intestine of fish using a coupled sodium gradient (Ash, 1985; Jobling, 1995). Documentation of xeno-
biotic transport by such systems is increasing. Transporters with structural and functional similarities to
multidrug resistance-associated proteins (Mrps), P-glycoprotein (Pgp), and organic anion transporter
polypeptides (Oatps) have been identified in fish (Ballatori et al., 1999; Curtis et al., 2000; Doi et al.,
2001; Hemmer et al., 1995; Kleinow et al., 2000; Masereeuw et al., 1999, 2000; Miller, 1995; Rebbeor
et al., 2000). These carriers may transport xenobiotics in the canaliculi of the liver, the mucosa of the
intestine, and the proximal tubule of the kidney. Additional carrier proteins have been associated with
the movement of metals in fish such as silver across the gill (Bury et al., 1999) and iron transport across
the yolk sac to the circulation (Donovan et al., 2000). Facilitated diffusion is a carrier-mediated process
that does not require energy. Movement of the transported compound may occur in either direction
across the membrane but the net movement follows the downhill electrochemical gradient much like
passive diffusion. Unlike passive diffusion, however, facilitated diffusion may be capacity limited because
the number of carriers is limited.

Pinocytosis
Pinocytosis is a process whereby the cell membrane invaginates, capturing external material within the
lumen of a vesicle. The vesicle may empty its contents within the cell or fuse with another portion of
the cell membrane, releasing its contents to the intercellular space. Uptake of macromolecular proteins
by pinocytosis is well documented in the fish intestine (Rombout et al., 1985; Stroband and Kroon,
1981; Stroband et al., 1979). It is likely that transport of particulate or proteinaceous toxicants in fish
occurs by this process, but verification is required.

Paracellular Pathway
Evidence in mammals suggests that tight junctions between neighboring cells are permeable to water,
inorganic cations, and to a limited extent xenobiotics (Hoensch and Schwenk, 1984). The degree to
which xenobiotics move by diffusion along these pathways is currently unknown for fishes.

Absorption, Distribution, and Excretion
Xenobiotic Absorption
Xenobiotics are absorbed by fish across the gills, skin, and gut. In terms of gross morphology, these
structures differ greatly from one another. All three, however, possess two basic features that contribute
to their role as chemical exchange surfaces: (1) large surface area, and (2) separation of the environment,
or extension thereof, from the circulatory system by a membrane consisting of one, two, or a few cell
layers. The path that a chemical takes when it is absorbed at one of these surfaces can be generally