STUDIES ON THE RENAL TRANSPORT OF TRIMETHYLPENTANOIC ACID METABOLITESOF 2,2,4-TRIMETHYLPENTANE IN RAT RENAL CORTICAL SLICES

2,2,4-Trimethylpentane (TMP), a nephrotoxic component of unleaded gaso line in male but not female rats, undergoes oxidative metabolism to yi eld 2,2,4- and 2,4,4-trimethylpentanol, pentanoic acid and 5-hydroxype ntanoic acid. We have examined the effect of three of these pentanoic acid metabolites on the renal transport of the organic anion p-aminohi ppurate (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 decre ase in the accumulation of PAH without affecting TEA accumulation. Kin etic analysis showed that 2,4,4-trimethylpenanoic acid was a competiti ve inhibitor of the organic anion transport system, with a K(i) of 4 m M. 2,4,4-Trimethyl-5-hydroxypentanoic acid also showed selective inhib ition of PAH transport, while 2,2,4-trimethylpentanoic acid was less s elective and reduced both PAH and TEA transport. Additional studies wi th radiolabeled 2,4,4-trimethylpentanoic acid showed that there was a time- and concentration-dependent accumulation of radioactivity into s lices of renal cortex. However, experiments conducted at 4-degrees-C a nd 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 t ransported 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.