Cholestyramine Protection against Ochratoxin A Toxicity: Role of Ochratoxin A Sorption by the Resin and Bile Acid Enterohepatic Circulation

Abstract

We have shown that the addition of cholestyramine (CHA, a resin known to bind bile salts in the gastrointestinal tract) to ochratoxin A (OTA)-contaminated rat diets reduced plasma levels of the toxin and prevented OTA-induced nephrotoxicity. To elucidate the mechanism of action of CHA, we carried out in vitro experiments to determine whether the resin may bind the toxin. For comparative purposes, binding of bile salts to the resin was also examined. Results showed that CHA binds both OTA and bile salts (taurodeoxycholate [TDC] and taurocholate [TCA]). Also, CHA showed greater affinity for OTA and TDC than for TCA. At 1 mM concentration, 96% of OTA and 80% of TDC were bound to the resin, while for TCA binding was only 50%. However, saturation of the resin was reached at higher levels with bile acids compared to OTA (3.67 mmol/g resin for TCA and 3.71 mmol/g resin for TDC versus 2.85 mmol/g resin for OTA). To characterize the nature of the binding of the toxin to CHA, NaCl (0 to 200 mM) was added to a fixed amount of OTA or bile acids. As expected, TCA absorption was decreased by the addition of NaCl (<50 mM), indicating electrostatic binding. However, OTA and TDC sorption was decreased only at high concentrations of NaCl (>150 mM), suggesting a stronger binding to the resin than that shown with TCA. Sequential competitive studies demonstrated that CHA binds more OTA than TCA. The results of the in vivo study show the role of bile salts in OTA absorption. The toxin's plasma levels at 1 and 3 h after a single oral dose of OTA were significantly decreased in bile salt-depleted rats compared to the control. Thus, the alteration of the bile salt biliary pool and OTA enterohepatic circulation may be an additional mechanism of action of the resin against mycotoxin toxicity.

Decreased biliary excretion of tributylmethyl ammonium in cholestyramine pretreated rats due to reduced formation of ion‐pair complexes with hepatic bile salts

“…The concentration of bile salts in the liver could be lowered by 48% (Table 1) by the oral administration of cholestyramine, which blocked the reabsorption of bile salts from the intestine [15,16]. It is noteworthy that the binding affinity of cholestyramine varies depending on the structure of the bile salt [17][18][19] with particularly large values for conjugated dihydroxy bile salts (e.g. taurodeoxycholate, TDC) [18,19], the bile salts most likely to form lipophilic ion-pair complexes with TBuMA in the liver [6].…”

“…It is noteworthy that the binding affinity of cholestyramine varies depending on the structure of the bile salt [17][18][19] with particularly large values for conjugated dihydroxy bile salts (e.g. taurodeoxycholate, TDC) [18,19], the bile salts most likely to form lipophilic ion-pair complexes with TBuMA in the liver [6]. Although the concentration of individual bile salts was not determined in the present study, the greater decrease in the levels of conjugated dihydroxy bile salts would not be surprising based on the stronger binding affinity of cholestyramine to these bile salts.…”

Possible estuary-associated syndrome: symptoms, vision, and treatment.

“…Confirmation of this hypothesis will not be possible until the toxin, or suite of toxins and their metabolites, are identified. There are intriguing studies under way (45,46) that focus on the three-dimensional structure of organic toxins and the existence of a molecular dipole in those toxins, particularly in polycyclic ether toxins identified in other dinoflagellate species (47) and in carboxylic acid ether toxins of fungal species (40,45,46), into which the quaternary ammonium side chain of CSM fits exactly, much as it fits into particular crown-6-ether structures (48). Further research is needed to clarify the mechanisms by which CSM leads to the elimination of the TPC and other organic toxins.…”

Distribution of Brevetoxin (PbTx-3) in Mouse Plasma: Association with High-Density Lipoproteins

“…In this light, another potential target for therapeutics is the enterohepatic recirculation pathway. Through the binding of bile salts and reduced intestinal reabsorption, bile acid sequestrants effectively disrupt this pathway and have been reported to reduce the symptoms of ochratoxin (Kerkadi et al 1998, 1999). Accordingly, targeting both pathways for reverse cholesterol transfer and enterohepatic recirculation may ultimately lead to the development of therapies to mitigate the symptoms of neurotoxic shellfish poisoning and ciguatera fish poisoning.…”