Page 109 - The Toxicology of Fishes

Toxicokinetics in Fishes 89

Anion Secretion Cation Secretion

ECF Proximal Lumen ECF Proximal Lumen
Cell Cell

+ + +
2K 3Na Na
~ ~
1 1 3
3Na + H +
3Na + CI – H +
2 ? 5 vesicle + ~
αKG = PAH – ? OC
αKG = + +
OC + H H
3 6 2 4
– – + +
PAH PAH OC OC
?
vesicle
PAH –
FX –
? OC +
– – ~
FX FX 5
4 ~ 7
–70 mV –70 mV

FIGURE 3.16 Mechanisms for renal secretion of organic anions and organic cations. Open circles represent carrier proteins,
the symbol ~ within a circle indicates an ATPase, and arrows show the preferred direction of transport. (A) Organic anion
–
secretion: The transport of p-aminohippuric acid (PAH ), a prototypical organic acid, is coupled to ATP hydrolysis and the
–2
–
movement of α-ketoglutarate (αKG ) (components 1 and 3). Larger organic acids, such as fluoroscein-methotrexate (FX ),
may enter the proximal tubule cell by a Na-independent path (4) or simple diffusion. Intracellular organic anions may
diffuse to the luminal membrane, bind to macromolecules, or be transported into vesicular structures. Uptake into vesicles
is carrier mediated but the mechanisms are unknown. Efflux to the lumen may occur by facilitated diffusion (6) or through
the activity of a drug-transporting ATPase such as Mrp2 (7). The luminal anion exchanger (5) is primarily responsible for
the reabsorption of urate but may play a role in the secretion of other anions. (B) Organic cation secretion: Facilitated
transport of an organic cation (OC ) across the basolateral membrane is favored by a negative membrane potential (2).
+
Some of the OC may be sequestered in vesicles; the rest is transported to the lumen by two pathways. The first pathway
+
+
+
+
involves H /OC exchange (4), which is driven by a pH gradient (3) that is coupled to the Na pump (1). The second
pathway involves the multidrug transport ATPase MDR (5). (Adapted from Pritchard, J.B., in The Textbook of Nephrology,
4th ed., Massry, S.G. and Glassock, R.J., Eds., Lippincott Williams & Wilkins, Baltimore, MD, 2001, pp. 93–97.)
–2
αKG gradient; and (3) the organic anion moves into the cell in exchange for the outward movement
of αKG . Efflux from the epithelial cells into the tubule may occur by facilitated diffusion. Other
–2
compounds are transported across the luminal membrane of the cell by the drug-transporting ATPase
Mrp2 (Miller and Pritchard, 1997).
Tubular Cation Secretion
Renal cation secretion is also a multistep process (Figure 3.16). In contrast to anion secretion, however,
chemical movement into the epithelial cell (by facilitated diffusion) is energetically favored because of
the strong negative charge on the cell interior. Movement into the lumen of the tubule is opposed by the
membrane potential and must be tied to the hydrolysis of ATP (Pritchard, 2001). As with anion secretion,
the cationic secretory system is highly susceptible to substrate competition.