Accurate identification of UDP-glucuronosyltransferase 1A1 (UGT1A1) inhibitors using UGT1A1-overexpressing HeLa cells

Abstract

1. UDP-glucuronosyltransferase 1A1 (UGT1A1) plays an irreplaceable role in detoxification of bilirubin and many drugs (e.g., SN-38). Here we aimed to explore the potential of UGT1A1-overexpressing HeLa cells (or HeLa1A1 cells) as a tool to accurately identify UGT1A1 inhibitors.

2. Determination of glucuronidation rates (β-estradiol and SN-38 as the substrates) was performed using HeLa1A1 cells and uridine diphosphoglucuronic acid (UDPGA)-supplemented cDNA expressed UGT1A1 enzyme (or microsomes). The inhibitory effects (IC₅₀ values) of 20 structurally diverse compounds on the UGT1A1 activity were determined using HeLa1A1 cells and microsomal incubations.

3. In HeLa1A1 cells, the IC₅₀ values for inhibition of β-estradiol glucuronidation by the tested compounds ranged from 0.33 to 94.6 µM. In the microsomal incubations, the IC₅₀ values ranged from 0.47 to 155 µM. It was found that the IC₅₀ values of all test compounds derived from the cells were well consistent with those from the microsomes (deviated by less than two-fold). Further, the IC₅₀ values from the cells were strongly correlated with those from microsomes (r = 0.944, p < 0.001). Likewise, the IC₅₀ values (0.37–77.3 µM) for inhibition of SN-38 glucuronidation in the cells were close to those (0.42–122 µM) for glucuronidation inhibition in microsomes. A strong correlation was also observed between the two sets of IC₅₀ values (r = 0.978, p < 0.001).

4. In conclusion, UGT1A1-overexpressing HeLa cells were an appropriate tool to accurately depict the inhibition profiles of chemicals against UGT1A1.

• Drug–drug interactions
• glucuronidation
• HeLa cells
• inhibitor identification
• UGT1A1

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

This work was supported by the Young Scientist Special Projects in biotechnological and pharmaceutical field of 863 Program (SS2015AA020916).