PERITUBULAR PARAQUAT TRANSPORT IN ISOLATED RENAL PROXIMAL TUBULES

To better understand the characteristics of peritubular transport of o rganic cations (OCs), the uptake of the polyvalent OC dimethylbipyridi nium (paraquat) and the structurally similar monovalent OC 1-methyl-4- phenylpyridinium (MPP(+)) was measured in suspensions of rabbit renal proximal tubules. Compared to the uptake of MPP(+), the uptake of para quat across the peritubular membrane was a low affinity, low capacity carrier-mediated process with a J(max) of 0.52 +/- 0.19 nmol . mg of p rotein .(-1)min(-1) and a K-m of 162 +/- 25 mu M. The uptake of MPP(+) was a carrier-mediated process with a measured J(max) and K-m of 1.8 +/- 0.09 nmol mg of protein (-1)min(-1) and 28 +/- 8 mu M, respectivel y. To determine whether paraquat is a substrate for the monovalent OC pathway, the effect of unlabeled MPP(+) and tetraethylammonium (TEA) o n paraquat uptake was examined. A 1 mM concentration of the monovalent OC MPP(+) and TEA reduced the uptake of [C-14]paraquat and [H-3]MPP() by similar to 30 and 90%, respectively, whereas 1 mM paraquat had no effect on [H-3]MPP(+) or [C-14]TEA uptake. Thus, MPP(+), but not para quat, appears to interact with the monovalent OC transporter. On the o ther hand, the polyvalent OC substrates, including the polyamines putr escine and spermine, the herbicide diquat and the divalent hexamethoni um bromidehydrate had no effect on either paraquat or MPP(+) uptake. H owever, the synthetic polyamine methylglyoxal bis(guanyl-hydrazone)dih ydrochloride (MGBG; 1 mM) reduced both paraquat and MPP(+) uptake (by 60 and 90%, respectively). The ability of MGBG, unlike the other polyv alent substrates, to interact with paraquat transport may be related t o structural similarities in the relative location of the two charged nitronium moieties in paraquat and MGBG. These observations, collectiv ely, suggest that paraquat is transported by a novel peritubular polyv alent OC transport system which may provide an additional mechanism by which the kidney can clear potentially harmful xenobiotics from the s ystemic circulation.