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Studies on the renal transport of trimethylpentanoic acid metabolites of 2,2,4‐trimethylpentane in rat renal cortical slices
Author(s) -
Lock Edward A.,
Strasser Josef,
Bus James S.,
Charbonneau Michel
Publication year - 1993
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.2550130412
Subject(s) - chemistry , metabolite , tetraethylammonium , renal cortex , metabolism , nephrotoxicity , organic anion , biochemistry , kidney , aminohippuric acid , organic acid , endocrinology , toxicity , organic chemistry , renal function , potassium , ion , biology
Abstract 2,2,4‐Trimethylpentane (TMP), a nephrotoxic component of unleaded gasoline in male but not female rats, undergoes oxidative metabolism to yield 2,2,4‐ and 2,4,4‐trimethylpentanol, pentanoic acid and 5‐hydroxypentanoic acid. We have examined the effect of three of these pentanoic acid metabolites on the renal transport of the organic anion p ‐aminohippurate (PAH) and the organic cation tetraethylammonium (TEA) in renal cortical slices from male Fischer 344 rats. 2,4,4‐Trimethylpentanoic acid, the major urinary metabolite in rats, produced a selective decrease in the accumulation of PAH without affecting TEA accumulation. Kinetic analysis showed that 2,4,4‐trimethylpenanoic acid was a competitive inhibitor of the organic anion transport system, with a K i of 4 mM. 2,4,4‐Trimethyl‐5‐hydroxypentanoic acid also showed selective inhibition of PAH transport, while 2,2,4‐trimethylpentanoic acid was less selective and reduced both PAH and TEA transport. Additional studies with radiolabeled 2,4,4‐trimethylpentanoic acid showed that there was a time‐and concentration‐dependent accumulation of radioactivity into slices of renal cortex. However, experiments conducted at 4°C and studies with metabolic inhibitors, or with an inhibitor of organic anion transport, indicated that little of the accumulated material was entering the cell. We conclude from these studies that the pentanoic acid metabolites formed from 2,2,4‐trimethylpentane are not actively transported by the renal organic anion transport system. In summary, in vitro the pentanoic acid metabolites appear to bind to renal cortical tissue and thereby reduce the transport of PAH.