Effect of halogenated vinyl cysteine conjugates on renal tubular active transport

Christopher D. Hassall; A. Jay Gandolfi; Klaus Brendel

doi:10.1016/0300-483X(83)90089-6

Effect of halogenated vinyl cysteine conjugates on renal tubular active transport

Christopher D. Hassall, A. Jay Gandolfi, Klaus Brendel

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

Addition of halogenated vinyl cysteine conjugates to isolated rabbit kidney tubule suspensions resulted in a decrease in the active transport of para-aminohippuric acid (PAH) and tetraethylammonium bromide (TEA). At 10^-5 M vinyl cysteine conjugate, tubule to medium accumulation ratios (T/M) were similar to those of controls while at 10^-3 M the T/M values decreased to 1, indicating complete inhibition of active acummulation of PAH or TEA. The decreased active transport was not caused by inhibition of mitochondrial oxidation since incubations in the presence of 10^-3 M halogenated vinyl cysteine did not inhibit tubule O₂ utilization or production of ¹⁴CO₂ from [¹⁴C]glucose or [¹⁴C]succinate. A mechanism is proposed whereby toxicity may result from covalent binding of an active intermediate, produced by enzyme cleavage, to membrane associated nucleophilic groups thereby decreasing active transport.

Original language	English (US)
Pages (from-to)	285-294
Number of pages	10
Journal	Toxicology
Volume	26
Issue number	3-4
DOIs	https://doi.org/10.1016/0300-483X(83)90089-6
State	Published - 1983

Keywords

1,2-Dichlorovinyl cysteine
Active transport
Bioactivation
DCVC
Halogenated vinyl cysteine
Mitochondrial respiration
Nephrotoxin
Renal tubule

ASJC Scopus subject areas

Toxicology

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10.1016/0300-483X(83)90089-6

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title = "Effect of halogenated vinyl cysteine conjugates on renal tubular active transport",

abstract = "Addition of halogenated vinyl cysteine conjugates to isolated rabbit kidney tubule suspensions resulted in a decrease in the active transport of para-aminohippuric acid (PAH) and tetraethylammonium bromide (TEA). At 10-5 M vinyl cysteine conjugate, tubule to medium accumulation ratios (T/M) were similar to those of controls while at 10-3 M the T/M values decreased to 1, indicating complete inhibition of active acummulation of PAH or TEA. The decreased active transport was not caused by inhibition of mitochondrial oxidation since incubations in the presence of 10-3 M halogenated vinyl cysteine did not inhibit tubule O2 utilization or production of 14CO2 from [14C]glucose or [14C]succinate. A mechanism is proposed whereby toxicity may result from covalent binding of an active intermediate, produced by enzyme cleavage, to membrane associated nucleophilic groups thereby decreasing active transport.",

keywords = "1,2-Dichlorovinyl cysteine, Active transport, Bioactivation, DCVC, Halogenated vinyl cysteine, Mitochondrial respiration, Nephrotoxin, Renal tubule",

author = "Hassall, {Christopher D.} and {Jay Gandolfi}, A. and Klaus Brendel",

note = "Funding Information: This work was funded by a grant from the National Instituteso f Health, AM 14977. The synthesis of halogenatedv inyl cysteine conjugatesw as funded by an AmericanC ancerSociety grant, ACS 110-B.",

year = "1983",

doi = "10.1016/0300-483X(83)90089-6",

language = "English (US)",

volume = "26",

pages = "285--294",

journal = "Toxicology",

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publisher = "Elsevier Ireland Ltd",

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T1 - Effect of halogenated vinyl cysteine conjugates on renal tubular active transport

AU - Hassall, Christopher D.

AU - Jay Gandolfi, A.

AU - Brendel, Klaus

N1 - Funding Information: This work was funded by a grant from the National Instituteso f Health, AM 14977. The synthesis of halogenatedv inyl cysteine conjugatesw as funded by an AmericanC ancerSociety grant, ACS 110-B.

PY - 1983

Y1 - 1983

N2 - Addition of halogenated vinyl cysteine conjugates to isolated rabbit kidney tubule suspensions resulted in a decrease in the active transport of para-aminohippuric acid (PAH) and tetraethylammonium bromide (TEA). At 10-5 M vinyl cysteine conjugate, tubule to medium accumulation ratios (T/M) were similar to those of controls while at 10-3 M the T/M values decreased to 1, indicating complete inhibition of active acummulation of PAH or TEA. The decreased active transport was not caused by inhibition of mitochondrial oxidation since incubations in the presence of 10-3 M halogenated vinyl cysteine did not inhibit tubule O2 utilization or production of 14CO2 from [14C]glucose or [14C]succinate. A mechanism is proposed whereby toxicity may result from covalent binding of an active intermediate, produced by enzyme cleavage, to membrane associated nucleophilic groups thereby decreasing active transport.

AB - Addition of halogenated vinyl cysteine conjugates to isolated rabbit kidney tubule suspensions resulted in a decrease in the active transport of para-aminohippuric acid (PAH) and tetraethylammonium bromide (TEA). At 10-5 M vinyl cysteine conjugate, tubule to medium accumulation ratios (T/M) were similar to those of controls while at 10-3 M the T/M values decreased to 1, indicating complete inhibition of active acummulation of PAH or TEA. The decreased active transport was not caused by inhibition of mitochondrial oxidation since incubations in the presence of 10-3 M halogenated vinyl cysteine did not inhibit tubule O2 utilization or production of 14CO2 from [14C]glucose or [14C]succinate. A mechanism is proposed whereby toxicity may result from covalent binding of an active intermediate, produced by enzyme cleavage, to membrane associated nucleophilic groups thereby decreasing active transport.

KW - 1,2-Dichlorovinyl cysteine

KW - Active transport

KW - Bioactivation

KW - DCVC

KW - Halogenated vinyl cysteine

KW - Mitochondrial respiration

KW - Nephrotoxin

KW - Renal tubule

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DO - 10.1016/0300-483X(83)90089-6

M3 - Article

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AN - SCOPUS:0020601541

SN - 0300-483X

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JO - Toxicology

JF - Toxicology

IS - 3-4

ER -

Effect of halogenated vinyl cysteine conjugates on renal tubular active transport

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Keywords

ASJC Scopus subject areas

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