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Ochratoxin A Secretion in Primary Cultures of Rabbit Renal Proximal Tubule Cells

CARLOTTA E. GROVES^*, GRAZYNA NOWAK and MARK MORALES^*

^* Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida.
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Correspondence to Dr. Carlotta E. Groves, University of Florida, College of Veterinary Medicine, Department of Physiological Sciences, Center for Environmental and Human Toxicology, P.O. Box 110885, Gainesville, FL 32611-0885. Phone: 352-392-4700 (ext. 5540); Fax: 352-392-4707; E-mail: grovesce{at}mail.vetmed.ufl.edu

Abstract. Primary cultures of rabbit renal proximal tubule cells grown under improved culture conditions were used to study the transepithelial transport of the nephrotoxic mycotoxin ochratoxin A. The basal-to-apical transepithelial flux, i.e., secretion, of this fluorescence organic acid was measured in primary cultures of rabbit renal proximal tubule cells. The basal-to-apical flux of ochratoxin A increased with time and reached a steady state after 12 h. On the other hand, the apical-to-basal flux, i.e., reabsorption, of ochratoxin A was minimal over time. The secretory flux of ochratoxin A was as much as eightfold greater than the reabsorptive flux, indicating that net secretion is the primary mechanism for ochratoxin A clearance by the proximal tubule. The kinetic analysis of ochratoxin A flux revealed secretion to be a saturable and very high-affinity process with an apparent K₅₀ of 0.33 ± 0.21 mM. A saturating concentration of the prototypical organic anion substrate para-aminohippurate (PAH) reduced ochratoxin A secretion by approximately 75%. The kinetic analysis of PAH inhibition of ochratoxin A secretion revealed an IC₅₀ of 195 mM, which is similar to the IC₅₀ for PAH inhibition of peritubular ochratoxin A uptake in tubule suspensions and the K_m values for peritubular PAH uptake. The organic anions probenecid, octanoate, and -ketoglutarate reduced ochratoxin A excretion to the same degree as PAH, whereas the amino acid phenylalanine had a minimal effect on ochratoxin A secretion. Thus, collectively, these observations indicate that the secretion of ochratoxin A in primary cultures of rabbit renal proximal tubules is limited to the organic anion secretory pathway. The high affinity measured for the basal-to-apical flux of ochratoxin A suggests that at concentrations typical of naturally occurring exposures, transepithelial secretion by the organic anion transport pathway represents a significant avenue for excretion of this mycotoxin by the renal proximal tubule.

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