Peritubular paraquat transport in isolated renal proximal tubules

C. E. Groves, M. N. Morales, A Jay Gandolfi, William H Dantzler, Stephen Wright

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

To better understand the characteristics of peritubular transport of organic cations (OCs), the uptake of the polyvalent OC dimethylbipyridinium (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 paraquat 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 protein · -1 min-1 and a K(m) of 162 ± 25 μM. 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. -1min-1 and 28 ± 8 μM, respectively. To determine whether paraquat is a substrate for the monovalent OC pathway, the effect of unlabeled MPP+ and tetraethylammonium (TEA) on paraquat uptake was examined. A 1 mM concentration of the monovalent OC MPP+ and TEA reduced the uptake of [14C]paraquat and [3H]MPP+ by ~ 30 and 90%, respectively, whereas 1 mM paraquat had no effect on [3H]MPP+ or [14C]TEA uptake. Thus, MPP+, but not paraquat, appears to interact with the monovalent OC transporter. On the other hand, the polyvalent OC substrates, including the polyamines putrescine and spermine, the herbicide diquat and the divalent hexamethonium bromidehydrate had no effect on either paraquat or MPP+ uptake. However, the synthetic polyamine methylglyoxal bis(guanyl-hydrazone)dihydrochloride (MGBG; 1 mM) reduced both paraquat and MPP+ uptake (by 60 and 90%, respectively). The ability of MGBG, unlike the other polyvalent substrates, to interact with paraquat transport may be related to structural similarities in the relative location of the two charged nitronium moieties in paraquat and MGBG. These observations, collectively, suggest that paraquat is transported by a novel peritubular polyvalent OC transport system which may provide an additional mechanism by which the kidney can clear potentially harmful xenobiotics from the systemic circulation.

Original languageEnglish (US)
Pages (from-to)926-932
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume275
Issue number2
StatePublished - 1995

Fingerprint

Proximal Kidney Tubule
Paraquat
Monovalent Cations
Mitoguazone
Tetraethylammonium
Cations
Polyamines
Diquat
1-Methyl-4-phenylpyridinium
Pyruvaldehyde
Hydrazones
Hexamethonium
Putrescine
Spermine
Herbicides
Xenobiotics
Suspensions
Proteins

ASJC Scopus subject areas

  • Pharmacology

Cite this

Peritubular paraquat transport in isolated renal proximal tubules. / Groves, C. E.; Morales, M. N.; Gandolfi, A Jay; Dantzler, William H; Wright, Stephen.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 275, No. 2, 1995, p. 926-932.

Research output: Contribution to journalArticle

@article{a5a024f82ea4467e9be84180405cb480,
title = "Peritubular paraquat transport in isolated renal proximal tubules",
abstract = "To better understand the characteristics of peritubular transport of organic cations (OCs), the uptake of the polyvalent OC dimethylbipyridinium (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 paraquat 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 protein · -1 min-1 and a K(m) of 162 ± 25 μM. 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. -1min-1 and 28 ± 8 μM, respectively. To determine whether paraquat is a substrate for the monovalent OC pathway, the effect of unlabeled MPP+ and tetraethylammonium (TEA) on paraquat uptake was examined. A 1 mM concentration of the monovalent OC MPP+ and TEA reduced the uptake of [14C]paraquat and [3H]MPP+ by ~ 30 and 90{\%}, respectively, whereas 1 mM paraquat had no effect on [3H]MPP+ or [14C]TEA uptake. Thus, MPP+, but not paraquat, appears to interact with the monovalent OC transporter. On the other hand, the polyvalent OC substrates, including the polyamines putrescine and spermine, the herbicide diquat and the divalent hexamethonium bromidehydrate had no effect on either paraquat or MPP+ uptake. However, the synthetic polyamine methylglyoxal bis(guanyl-hydrazone)dihydrochloride (MGBG; 1 mM) reduced both paraquat and MPP+ uptake (by 60 and 90{\%}, respectively). The ability of MGBG, unlike the other polyvalent substrates, to interact with paraquat transport may be related to structural similarities in the relative location of the two charged nitronium moieties in paraquat and MGBG. These observations, collectively, suggest that paraquat is transported by a novel peritubular polyvalent OC transport system which may provide an additional mechanism by which the kidney can clear potentially harmful xenobiotics from the systemic circulation.",
author = "Groves, {C. E.} and Morales, {M. N.} and Gandolfi, {A Jay} and Dantzler, {William H} and Stephen Wright",
year = "1995",
language = "English (US)",
volume = "275",
pages = "926--932",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Peritubular paraquat transport in isolated renal proximal tubules

AU - Groves, C. E.

AU - Morales, M. N.

AU - Gandolfi, A Jay

AU - Dantzler, William H

AU - Wright, Stephen

PY - 1995

Y1 - 1995

N2 - To better understand the characteristics of peritubular transport of organic cations (OCs), the uptake of the polyvalent OC dimethylbipyridinium (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 paraquat 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 protein · -1 min-1 and a K(m) of 162 ± 25 μM. 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. -1min-1 and 28 ± 8 μM, respectively. To determine whether paraquat is a substrate for the monovalent OC pathway, the effect of unlabeled MPP+ and tetraethylammonium (TEA) on paraquat uptake was examined. A 1 mM concentration of the monovalent OC MPP+ and TEA reduced the uptake of [14C]paraquat and [3H]MPP+ by ~ 30 and 90%, respectively, whereas 1 mM paraquat had no effect on [3H]MPP+ or [14C]TEA uptake. Thus, MPP+, but not paraquat, appears to interact with the monovalent OC transporter. On the other hand, the polyvalent OC substrates, including the polyamines putrescine and spermine, the herbicide diquat and the divalent hexamethonium bromidehydrate had no effect on either paraquat or MPP+ uptake. However, the synthetic polyamine methylglyoxal bis(guanyl-hydrazone)dihydrochloride (MGBG; 1 mM) reduced both paraquat and MPP+ uptake (by 60 and 90%, respectively). The ability of MGBG, unlike the other polyvalent substrates, to interact with paraquat transport may be related to structural similarities in the relative location of the two charged nitronium moieties in paraquat and MGBG. These observations, collectively, suggest that paraquat is transported by a novel peritubular polyvalent OC transport system which may provide an additional mechanism by which the kidney can clear potentially harmful xenobiotics from the systemic circulation.

AB - To better understand the characteristics of peritubular transport of organic cations (OCs), the uptake of the polyvalent OC dimethylbipyridinium (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 paraquat 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 protein · -1 min-1 and a K(m) of 162 ± 25 μM. 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. -1min-1 and 28 ± 8 μM, respectively. To determine whether paraquat is a substrate for the monovalent OC pathway, the effect of unlabeled MPP+ and tetraethylammonium (TEA) on paraquat uptake was examined. A 1 mM concentration of the monovalent OC MPP+ and TEA reduced the uptake of [14C]paraquat and [3H]MPP+ by ~ 30 and 90%, respectively, whereas 1 mM paraquat had no effect on [3H]MPP+ or [14C]TEA uptake. Thus, MPP+, but not paraquat, appears to interact with the monovalent OC transporter. On the other hand, the polyvalent OC substrates, including the polyamines putrescine and spermine, the herbicide diquat and the divalent hexamethonium bromidehydrate had no effect on either paraquat or MPP+ uptake. However, the synthetic polyamine methylglyoxal bis(guanyl-hydrazone)dihydrochloride (MGBG; 1 mM) reduced both paraquat and MPP+ uptake (by 60 and 90%, respectively). The ability of MGBG, unlike the other polyvalent substrates, to interact with paraquat transport may be related to structural similarities in the relative location of the two charged nitronium moieties in paraquat and MGBG. These observations, collectively, suggest that paraquat is transported by a novel peritubular polyvalent OC transport system which may provide an additional mechanism by which the kidney can clear potentially harmful xenobiotics from the systemic circulation.

UR - http://www.scopus.com/inward/record.url?scp=0029610126&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029610126&partnerID=8YFLogxK

M3 - Article

VL - 275

SP - 926

EP - 932

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -