Dehydroabietic acid, a major anionic contaminant of pulp mill effluent, reduces both active p-aminohippurate transport and passive membrane permeability in isolated renal membranes.
The renal organic anion transport system plays a pivotal role in elimination of potentially toxic anions. This system is driven by indirect coupling to the sodium gradient at the basolateral membrane, i.e., the organic anion enters the cell in exchange for internal alpha-ketoglutarate (alpha KG) and the in greater than out alpha KG gradient is regenerated by Na+/alpha KG cotransport. The resin acid, dehydroabietic acid (DHAA), is one of several anionic xenobiotics which enter the environment secondary to pulp and paper processing. Because it is largely ionized at neutral pH (pKa, 5.7), DHAA should share the organic anion system. Indeed, Na+/glutarate-coupled p-aminohippurate (PAH) uptake by renal basolateral membrane vesicles was inhibited competitively by DHAA (Ki congruent to 150 microM). Despite the reduced rate of PAH uptake, a substantial, but delayed, overshoot was observed, suggesting additional effects. Passive permeabilities to mannitol, PAH and sodium were all decreased by DHAA, consistent with a general tightening of the membrane. Decreased permeability extended the effective lifetime of imposed ion gradients. Thus, sodium driven glutarate uptake was stimulated by 200 microM DHAA, prolonging and more than doubling its overshoot. Because the immediate driving force for PAH uptake into basolateral membrane vesicles is the magnitude of the glutarate gradient, DHAA increased the driving force for PAH uptake and permitted a substantial overshoot despite the reduced rate of PAH uptake. These data indicate that DHAA has several distinctly different effects on the membrane.
Comparative Membrane Pharmacology Section, National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
J B
JB
Pritchard
R
R
Walden
A
A
Oikari
D045784:Abietanes; D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D007656:Ketoglutaric Acids / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008353:Mannitol / Q000378:metabolism; D008871:Microvilli / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D010130:p-Aminohippuric Acid / Q000378:metabolism*
D045784:Abietanes; D004224:Diterpenes; D007656:Ketoglutaric Acids; C013913:dehydroabietic acid; D008353:Mannitol; D010130:p-Aminohippuric Acid