Environmental Health Perspectives
Initial in Oi'o studies showed that the polar DDT metabolite, DDA (2, 2-bis-p-chlorophenyl acetic acid), was distributed very differently from DDT in the winter flounder, Pseudopleuronectes Americanuis. In particular, its urinary excretion was nearly 250 times DDT excretion. Its structure and polarity suggested that transport of DDA on the renal organic acid system might explain these results. Using isolated flounder renal tubules as a test system, extensive accumulation of DDA was shown.
... -to-medium ratios reached 15-20. This accumulation was inhibited by metabolic inhibitors and by other organic acids. Autoradiography demonstrated that the bulk of this uptake was intracellular and showed directly that cyanide and organic acids reduced intracellular DDA. Kinetic studies demonstrated that DDA competitively inhibited renal p-aminohippurate uptake. Its potency as an inhibitor was more than half that of probenecid, a potent inhibitor of this system. On the basis of these results a model of renal DDA secretion was proposed. This model predicted that DDA and ch mically similar compounds such as 2,4-dichlorophenoxy acetic acid (2,4-D) should also inhibit organic acid transport at other sites. A particularly crucial site might be the choroid plexus where acidic metabolites of serotonin and dopamine are secreted from the cerebrospinal fluid into the blood for subsequent elimination elsewherx. Both DDA and 2,4-D were shown to inhibit rabbit choroid plexus transport of the serotonin metabolite, 5-hydroxy-3-indole acetic acid (HIAA). Related compounds which are not organic anions such as the parent amine, serotonin, or the parent pesticide, DDT, were not inhibitory. Similarly, dieldrin did not inhibit HIAA transport, although it is reported to alter HIAA levels in Oi'o. Probenecid and other organic acids were all inhibitory. Kinetic techniques showed competition between the transported anion, HIAA, and DDA or 2,4-D. Thus, as in flounder kidney, DDA inhibits through its interaction with the organic acid carrier.