Peritubular transport of ochratoxin A by single rabbit renal proximal tubules

Epifluorescence microscopy was used to study peritubular transport of the fluorescent mycotoxin ochratoxin A (OTA) into single proximal tubule segments of the rabbit. Initial rates of OTA uptake into S2 segments were saturable and adequately described by Michaelis-Menten kinetics, with an apparent K...

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Veröffentlicht in:Journal of the American Society of Nephrology 1998-11, Vol.9 (11), p.1973-1982
Hauptverfasser: WELBORN, J. R, GROVES, C. E, WRIGHT, S. H
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container_end_page 1982
container_issue 11
container_start_page 1973
container_title Journal of the American Society of Nephrology
container_volume 9
creator WELBORN, J. R
GROVES, C. E
WRIGHT, S. H
description Epifluorescence microscopy was used to study peritubular transport of the fluorescent mycotoxin ochratoxin A (OTA) into single proximal tubule segments of the rabbit. Initial rates of OTA uptake into S2 segments were saturable and adequately described by Michaelis-Menten kinetics, with an apparent Km of 2.2+/-0.3 microM (SEM). Several lines of evidence indicated that peritubular uptake of OTA in S2 segments was effectively limited to the "classical" organic anion transporter. First, 5 mM p-aminohippurate (PAH) cis-inhibited the uptake of 1 microM OTA into tubules by 96%. Kinetic analysis of the inhibition of OTA uptake by PAH (100 microM to 5 mM) yielded an apparent Ki of 164 microM, similar to the 100 to 200 microM range of Km values previously reported for the peritubular uptake of PAH. Second, efflux of OTA from tubules was trans-stimulated 3.2-fold by the presence of 2.5 mM PAH in the uptake medium. Third, 100 microM alpha-ketoglutarate (alphaKG) trans-stimulated the uptake rate of 1 microM OTA by 1.8-fold. Fourth, besides PAH, other organic anions effectively cis-inhibited the uptake of 1 microM OTA into tubules (inhibitor, % inhibition): 1.5 mM alphaKG, 80%; 1 mM probenecid, 100%; 1 mM piroxicam, 100%; 1 mM octanoate, 100%. In contrast, 1.5 mM tetraethylammonium, an organic cation, blocked uptake of 1 microM OTA by only 7%. The inhibition of OTA uptake into S1 and S3 segments of the proximal tubule was qualitatively similar: 5 mM PAH cis-inhibited the uptake of 1 microM OTA by approximately 95% in both S1 and S3 segments. Thus, peritubular OTA uptake into all segments of the proximal tubule appears to be dominated by its interaction with the classical organic anion transporter. The high-affinity and relatively high capacity of this pathway for OTA suggest that peritubular uptake may be a significant avenue for the entry of this toxin into proximal tubule cells.
doi_str_mv 10.1681/ASN.V9111973
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R ; GROVES, C. E ; WRIGHT, S. H</creator><creatorcontrib>WELBORN, J. R ; GROVES, C. E ; WRIGHT, S. H</creatorcontrib><description>Epifluorescence microscopy was used to study peritubular transport of the fluorescent mycotoxin ochratoxin A (OTA) into single proximal tubule segments of the rabbit. Initial rates of OTA uptake into S2 segments were saturable and adequately described by Michaelis-Menten kinetics, with an apparent Km of 2.2+/-0.3 microM (SEM). Several lines of evidence indicated that peritubular uptake of OTA in S2 segments was effectively limited to the "classical" organic anion transporter. First, 5 mM p-aminohippurate (PAH) cis-inhibited the uptake of 1 microM OTA into tubules by 96%. Kinetic analysis of the inhibition of OTA uptake by PAH (100 microM to 5 mM) yielded an apparent Ki of 164 microM, similar to the 100 to 200 microM range of Km values previously reported for the peritubular uptake of PAH. Second, efflux of OTA from tubules was trans-stimulated 3.2-fold by the presence of 2.5 mM PAH in the uptake medium. Third, 100 microM alpha-ketoglutarate (alphaKG) trans-stimulated the uptake rate of 1 microM OTA by 1.8-fold. Fourth, besides PAH, other organic anions effectively cis-inhibited the uptake of 1 microM OTA into tubules (inhibitor, % inhibition): 1.5 mM alphaKG, 80%; 1 mM probenecid, 100%; 1 mM piroxicam, 100%; 1 mM octanoate, 100%. In contrast, 1.5 mM tetraethylammonium, an organic cation, blocked uptake of 1 microM OTA by only 7%. The inhibition of OTA uptake into S1 and S3 segments of the proximal tubule was qualitatively similar: 5 mM PAH cis-inhibited the uptake of 1 microM OTA by approximately 95% in both S1 and S3 segments. Thus, peritubular OTA uptake into all segments of the proximal tubule appears to be dominated by its interaction with the classical organic anion transporter. 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R</creatorcontrib><creatorcontrib>GROVES, C. E</creatorcontrib><creatorcontrib>WRIGHT, S. H</creatorcontrib><title>Peritubular transport of ochratoxin A by single rabbit renal proximal tubules</title><title>Journal of the American Society of Nephrology</title><addtitle>J Am Soc Nephrol</addtitle><description>Epifluorescence microscopy was used to study peritubular transport of the fluorescent mycotoxin ochratoxin A (OTA) into single proximal tubule segments of the rabbit. Initial rates of OTA uptake into S2 segments were saturable and adequately described by Michaelis-Menten kinetics, with an apparent Km of 2.2+/-0.3 microM (SEM). Several lines of evidence indicated that peritubular uptake of OTA in S2 segments was effectively limited to the "classical" organic anion transporter. First, 5 mM p-aminohippurate (PAH) cis-inhibited the uptake of 1 microM OTA into tubules by 96%. Kinetic analysis of the inhibition of OTA uptake by PAH (100 microM to 5 mM) yielded an apparent Ki of 164 microM, similar to the 100 to 200 microM range of Km values previously reported for the peritubular uptake of PAH. Second, efflux of OTA from tubules was trans-stimulated 3.2-fold by the presence of 2.5 mM PAH in the uptake medium. Third, 100 microM alpha-ketoglutarate (alphaKG) trans-stimulated the uptake rate of 1 microM OTA by 1.8-fold. Fourth, besides PAH, other organic anions effectively cis-inhibited the uptake of 1 microM OTA into tubules (inhibitor, % inhibition): 1.5 mM alphaKG, 80%; 1 mM probenecid, 100%; 1 mM piroxicam, 100%; 1 mM octanoate, 100%. In contrast, 1.5 mM tetraethylammonium, an organic cation, blocked uptake of 1 microM OTA by only 7%. The inhibition of OTA uptake into S1 and S3 segments of the proximal tubule was qualitatively similar: 5 mM PAH cis-inhibited the uptake of 1 microM OTA by approximately 95% in both S1 and S3 segments. Thus, peritubular OTA uptake into all segments of the proximal tubule appears to be dominated by its interaction with the classical organic anion transporter. 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H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-e78a0e2987b2907ccbee081f041f3f8b8722f6a47c38fe3fcf9252a4e54076eb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Animals</topic><topic>Anions - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Biological Transport - drug effects</topic><topic>Biological Transport - physiology</topic><topic>Collagenases - pharmacology</topic><topic>Contrast Media</topic><topic>Fluorescein - pharmacokinetics</topic><topic>Investigative techniques, diagnostic techniques (general aspects)</topic><topic>Ketoglutaric Acids - pharmacology</topic><topic>Kidney Tubules, Proximal - drug effects</topic><topic>Kidney Tubules, Proximal - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mycotoxins - pharmacokinetics</topic><topic>Ochratoxins - antagonists &amp; inhibitors</topic><topic>Ochratoxins - pharmacokinetics</topic><topic>p-Aminohippuric Acid - pharmacology</topic><topic>Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques</topic><topic>Rabbits</topic><topic>Stereoisomerism</topic><topic>Tetraethylammonium - pharmacology</topic><topic>Time Factors</topic><topic>Urinary system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>WELBORN, J. R</creatorcontrib><creatorcontrib>GROVES, C. E</creatorcontrib><creatorcontrib>WRIGHT, S. H</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of the American Society of Nephrology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>WELBORN, J. R</au><au>GROVES, C. E</au><au>WRIGHT, S. H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Peritubular transport of ochratoxin A by single rabbit renal proximal tubules</atitle><jtitle>Journal of the American Society of Nephrology</jtitle><addtitle>J Am Soc Nephrol</addtitle><date>1998-11-01</date><risdate>1998</risdate><volume>9</volume><issue>11</issue><spage>1973</spage><epage>1982</epage><pages>1973-1982</pages><issn>1046-6673</issn><eissn>1533-3450</eissn><coden>JASNEU</coden><abstract>Epifluorescence microscopy was used to study peritubular transport of the fluorescent mycotoxin ochratoxin A (OTA) into single proximal tubule segments of the rabbit. Initial rates of OTA uptake into S2 segments were saturable and adequately described by Michaelis-Menten kinetics, with an apparent Km of 2.2+/-0.3 microM (SEM). Several lines of evidence indicated that peritubular uptake of OTA in S2 segments was effectively limited to the "classical" organic anion transporter. First, 5 mM p-aminohippurate (PAH) cis-inhibited the uptake of 1 microM OTA into tubules by 96%. Kinetic analysis of the inhibition of OTA uptake by PAH (100 microM to 5 mM) yielded an apparent Ki of 164 microM, similar to the 100 to 200 microM range of Km values previously reported for the peritubular uptake of PAH. Second, efflux of OTA from tubules was trans-stimulated 3.2-fold by the presence of 2.5 mM PAH in the uptake medium. Third, 100 microM alpha-ketoglutarate (alphaKG) trans-stimulated the uptake rate of 1 microM OTA by 1.8-fold. Fourth, besides PAH, other organic anions effectively cis-inhibited the uptake of 1 microM OTA into tubules (inhibitor, % inhibition): 1.5 mM alphaKG, 80%; 1 mM probenecid, 100%; 1 mM piroxicam, 100%; 1 mM octanoate, 100%. In contrast, 1.5 mM tetraethylammonium, an organic cation, blocked uptake of 1 microM OTA by only 7%. The inhibition of OTA uptake into S1 and S3 segments of the proximal tubule was qualitatively similar: 5 mM PAH cis-inhibited the uptake of 1 microM OTA by approximately 95% in both S1 and S3 segments. Thus, peritubular OTA uptake into all segments of the proximal tubule appears to be dominated by its interaction with the classical organic anion transporter. The high-affinity and relatively high capacity of this pathway for OTA suggest that peritubular uptake may be a significant avenue for the entry of this toxin into proximal tubule cells.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams &amp; Wilkins</pub><pmid>9808082</pmid><doi>10.1681/ASN.V9111973</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1046-6673
ispartof Journal of the American Society of Nephrology, 1998-11, Vol.9 (11), p.1973-1982
issn 1046-6673
1533-3450
language eng
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source MEDLINE; EZB-FREE-00999 freely available EZB journals
subjects Animals
Anions - pharmacology
Biological and medical sciences
Biological Transport - drug effects
Biological Transport - physiology
Collagenases - pharmacology
Contrast Media
Fluorescein - pharmacokinetics
Investigative techniques, diagnostic techniques (general aspects)
Ketoglutaric Acids - pharmacology
Kidney Tubules, Proximal - drug effects
Kidney Tubules, Proximal - metabolism
Male
Medical sciences
Mycotoxins - pharmacokinetics
Ochratoxins - antagonists & inhibitors
Ochratoxins - pharmacokinetics
p-Aminohippuric Acid - pharmacology
Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
Rabbits
Stereoisomerism
Tetraethylammonium - pharmacology
Time Factors
Urinary system
title Peritubular transport of ochratoxin A by single rabbit renal proximal tubules
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