Irinotecan-induced bile acid malabsorption is associated with down-regulation of ileal Asbt (Slc10a2) in mice

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Abstract

Irinotecan, (CPT-11), an antitumor agent primarily used for the treatment of solid tumors, has often compromised clinical application due to the inducement of severe delay-onset diarrhea. Bile acid malabsorption (BAM) is widely accepted as the common cause of diarrhea. However, whether CPT-11-induced diarrhea has correlation with BAM is unknown. The aim of this study was to investigate the effect of CPT-11 on the bile acid homeostasis in mice. The mice were administrated with CPT-11 intravenously for four consecutive days. The total bile acids (TBAs) levels in the small intestine, colon, feces, liver, serum and gallbladder were evaluated by automatic biochemical analyzer, and the individual bile acids were also measured by LC-MS/MS. Real-time qPCR and Western blot techniques were used to evaluate the mRNA and protein expressions of Cyp7a1, Cyp27a1, Asbt, Ostα/β. In situ loop method was carried out to evaluate the function of apical Na+-dependent bile salt transporter (Asbt). Results showed that the bile acid pool size was significantly reduced by 17%, 25%, and 40% respectively at 2, 3, and 4 days post CPT-11 treatment. The fecal excretions of TBAs were significantly increased by 2.1-fold at 3 and 4 days post CPT-11 treatment. The ileal expression of Asbt was significantly decreased at mRNA and protein levels, and the transport ability of Asbt was also attenuated after CPT-11 treatment. Moreover, the incidence of CPT-11-induced delay-onset diarrhea was also decreased after cholestyramine administration in CPT-11-treated mice. These results indicated that BAM may be partially responsible for CPT-11-induced delay-onset diarrhea, and the underlying mechanism may have correlation with down-regulation of the Asbt in the ileum of mice.

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