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Cytotoxicity of S-(1,2,3,4,4-pentachlorobutadienyl)-L cysteine after apical and basolateral exposure of LLC-PK monolayers. Involvement of an amino acid transport system. 1990

J J Mertens, and E A Keukens, and M Appel, and B Spenkelink, and J H Temmink, and P J van Bladeren
Dept. of Toxicology, Agricultural University Wageningen, The Netherlands.

Glutathione conjugation and subsequent formation of cysteine conjugates are key steps in the nephrotoxicity of halogenated alkenes. In this metabolic activation several organs are involved. However little is known about the transporters responsible for the uptake of cysteine conjugates. Recent evidence suggest that amino acid transporters play a role in this uptake. Monolayers of LLC-PK1 cells, a kidney cell line, were exposed to S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine (PCBD-CYS). Cytotoxicity was used as a parameter for PCBD-CYS uptake. Basolateral exposure (1 h: 400 microM and 16 h: 25 microM) to PCBD-CYS resulted in a much higher aminooxyacetic acid inhibitable cytotoxicity than apical exposure, suggesting a preferential basolateral uptake of PCBD-CYS. Exposure to PCBD-CYS in the absence of sodium did not result in a decrease of the cytotoxicity, suggesting a sodium independency of the PCBD-CYS uptake. Amino acids and amino acid analogues were used as diagnostic compounds in the further identification of the PCBD-CYS transporter. In cis-inhibition experiments monolayers were co-incubated with PCBD-CYS and these diagnostic compounds during one hour. System L substrates such as 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH) and cycloleucine did not inhibit cytotoxicity. D-Tryptophan, a model inhibitor of System T, caused a strong inhibition. System L has, in contrast to System T, a high sensitivity to trans-stimulation. Pre-loading the monolayers with the diagnostic compounds should cause an increase in cytotoxicity when System L is involved. Neither System L substrates such as BCH and cycloleucine nor D-tryptophan increased cytotoxicity. These results suggest a preferential basolateral uptake of PCBD-CYS in LLC-PK1 monolayers and involvement of an amino acid transporter with characteristics of System T.

UI MeSH Term Description Entries
D007674 Kidney Diseases Pathological processes of the KIDNEY or its component tissues. Disease, Kidney,Diseases, Kidney,Kidney Disease
D002070 Butadienes Four carbon unsaturated hydrocarbons containing two double bonds. Butadiene Derivative,Butadiene Derivatives,Derivative, Butadiene,Derivatives, Butadiene
D002352 Carrier Proteins Proteins that bind or transport specific substances in the blood, within the cell, or across cell membranes. Binding Proteins,Carrier Protein,Transport Protein,Transport Proteins,Binding Protein,Protein, Carrier,Proteins, Carrier
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D003545 Cysteine A thiol-containing non-essential amino acid that is oxidized to form CYSTINE. Cysteine Hydrochloride,Half-Cystine,L-Cysteine,Zinc Cysteinate,Half Cystine,L Cysteine
D000596 Amino Acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Amino Acid,Acid, Amino,Acids, Amino
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001692 Biological Transport The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments. Transport, Biological,Biologic Transport,Transport, Biologic
D012964 Sodium A member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. Sodium Ion Level,Sodium-23,Ion Level, Sodium,Level, Sodium Ion,Sodium 23

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