HETEROGENEOUS METABOLISM AND TOXICITY OF 4-PENTENOATE ALONG THE DOG NEPHRON

4-Pentenoate (4P) is a short-chain fatty acid which causes a complete renal Fanconi syndrome. We have examined the mechanism of 4P toxicity along the nephron after a prolonged (30 min) exposition of isolated re nal tubular segments to this agent. In proximal tubules, 4P inhibited the activity of alpha-ketoglutarate dehydrogenase, pyruvate dehydrogen ase, and beta-oxidation, but not in thick ascending limb or inner medu llary collecting duct tubules in suspension. These proximal effects we re accompanied by a marked oxidation of the proximal redox state, with a fall in the tissue respiration and a low content of ATP. The acetyl -CoA content of proximal tubules was simultaneously reduced. Butyrate, acetate, hexanoate or octanoate did not exert these effects. In proxi mal tubules the metabolism of 4P led to the tissue accumulation of 3-k eto-4-pentenoyl-CoA, a known unspecific inhibitor of metabolic oxidati on. This metabolite was not detectable in thick ascending limbs which metabolized 4P rapidly. No metabolism of 4P was noted in collecting du cts. We conclude that beta-oxidation probably differs in proximal and thick ascending limb tubules, allowing 4P metabolism to exert a specif ic toxicity in proximal tubules. A selective proximal defect in energy metabolism probably explains the Fanconi syndrome observed with expos ition to 4P.