INHIBITION OF RENAL XENOBIOTIC EXCRETION BY TETRACHLOROGUAIACOL: MECHANISM AND POSSIBLE CONSEQUENCES

摘要

The weak acid tetrachloroguaiacol (teCG; pK_a 6.0) is the major chlorinated phenol produced during chlorine bleaching of wood pulp. Upon its release into the environment, it is persistent and markedly bioaccumulated (100- to 1,000-fold). Within the organism (pH ～7.4), it should be >95% ionized, making it a likely inhibitor of renal organic anion transport. Its effects on both passive membrane permeability and mediated transport processes were determined in basolateral (BLM) and luminal membrane (BBM) vesicles isolated from the rat kidney cortex. Vesicular solute uptake was measured by the rapid filtration technique at pH 7.5. Passive membrane permeability (assessed by mannitol uptake) was altered only at very high concentrations of teCG (? 1,000 μM). In contrast, transport of the model organic anion p-aminohippurate (PAH) by BLM vesicles was significantly inhibited by as little as 5 μM (1.3 mg/L) teCG and totally abolished by 200 μM. Inhibition was competitive (K_i = 31.3 μM). Decreasing assay pH diminished inhibition of the PAH uptake, reflecting the reduced concentration of ionized teCG. Other membrane effects were seen at higher teCG concentrations (>100 μM). The BLM sodium/glutarate cotransport was modestly, but significantly, stimulated by 100 to 500 μM teCG, whereas BBM sodium/glucose cotransport was inhibited by similar teCG concentrations. Thus, teCG has multiple effects on renal membrane function. However, at environmental levels (0.1 to 30 μM in plasma), its principal membrane effects would be related to changes in organic anion secretion.