Chlorogenic acid Disrupts the Metabolic Elimination of Drugs Used to Treat Gastrointestinal Cancer

Irinotecan is the first-line drug used to treat gastrointestinal cancer, and the toxicity severely limited the clinical utilization of irinotecan, such as diarrhea. The toxicity of irinotecan is closely related with carboxylesterases (CES)-catalyzed hydrolysis of irinotecan to form its active metabolite SN-38. This study aims to show the potential therapeutic function of chlorogenic acid on irinotecan-induced toxicity. Metabolomics analysis has shown that treatment of chlorogenic acid can significantly increase the plasma concentration of bile acids components LCA and THDCA. The inhibition of LCA and THDCA on the activity of CES1 was furtherly investigated. The results showed that the concentrations of bile acids LCA and THDCA significantly increased in chlorogenic acid-treated mice in comparison with control group. LCA 100 mu M significantly inhibited the activity of CES1 (p < 0.05). However, 100 mu M of THDCA did not show any inhibition potential towards the activity of CES1. The metabolic reaction velocity (v) was determined at different concentrations of LCA and BMBT, and Lineweaver-Burk plot was drawn using 1/v versus 1/[4-MU] at different concentrations of LCA. The intersection point was located in the verticle axis of Lineweaver-Burk plot, indicating the competitive inhibition of LCA on the activity of CES1. The second plot was drawn using the slopes of Lineweaver-Burk plot versus the concentrations of LCA, and the fitting equation was y = 0.823x + 83.22. Based on this equation, the inhibition kinetic parameters (Ki) were calculated to be 101.1 mu M. In conclusion, this study demonstrated the influence of chlorogenic acid on the metabolic profile of bile acids, and the level of LCA and THDCA significantly increased in chlorogenic acid-treated mice. This study demonstrated the inhibition of LCA on the activity of CES1. This study provides a new therapeutic potential of chlorogenic acid on irinotecan-induced toxicity, and also gave a new perspective to elucidate the protective function of chlorogenic acid on irinotecan-induced toxicity.