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Comprehensive Evaluation of Bile Acid Homeostasis in Human Hepatocyte Co-Culture in the Presence of Troglitazone, Pioglitazone and Acetylsalicylic Acid.

Interruption of bile acid (BA) homeostasis has been hypothesized for a variety of liver diseases and for drug-induced liver injury (DILI). Consequently, BA is gaining increasing prominence as a potential biomarker. The objective of this work was to evaluate the effect of troglitazone (TZN, associated with severe DILI), pioglitazone (PZN, rarely associated with DILI), and acetylsalicylic acid (ASA, or aspirin, not associated with DILI), on the in-vitro BA homeostasis in hepatocytes co-cultured with non-parenchymal cells by monitoring the disposition of 36 BAs. Cells were supplemented with 2.5 µM D4-cholic acid (D4-CA), D4-chenodeoxycholic acid (D4-CDCA), D4-lithocholic acid (D4-LCA), D4-deoxycholic acid (D4-DCA), D4-ursodeoxycholic acid (D4-UDCA) and hyodeoxycholic acid (HDCA). Concentration-time profiles of BAs were used to determine AUC from supernatant, lysate or bile compartments, in the presence or absence of TZN, PZN or ASA. When applicable, IC50 describing depletion of individual BAs was calculated, or accumulation greater than 200% of DMSO control was noted. Thiazolidinediones significantly altered the concentration of glycine and sulfate conjugates; however, more BAs were impacted by TZN than with PZN. For commonly shared BAs, TZN exhibited 3- to 13-fold stronger inhibition than PZN. In contrast, no changes were observed with ASA. Modulation of BA disposition by thiazolidinediones and ASA was appropriately differentiated. Particularly for thiazolidinediones, TZN was more potent in interrupting BA homeostasis, and when also considering its higher dose, may explain differences in their clinical instances of DILI. This is one of the first work which comprehensively evaluated the disposition of primary and secondary BAs along with their metabolites in an in vitro system. Differing degree of BA homeostasis modulation was observed with various perpetrators associated with varying clinical instances of DILI. These data indicate that in vitro systems such as hepatocyte co-cultures may be a promising tool to gain detailed insight into how drugs effect BA handling to further probe into the mechanism of DILI related to BA homeostasis.