Ovarian Cancer Treatment Drug 13-Cis Retinoic Acid Showed Inhibition on the Activity of UDP-Glucuronosyltransferases (UGTs)

Ovarian cancer is forming in the ovary, which challenges the health of women. 13-cis retinoic acid (isotretinoin) is a potential drug for treatment of ovarian cancer. This study aims to determine the inhibition of 13-cis retinoic on the activity of UDP-glucuronosyltransferase (UGT) 1A6 and 2B7, trying to indicate the potential adverse effects. In vitro recombinant UGT1A6 and UGT2B7-catalyzed glucuronidation of 4-methylumbelliferone was used as the probe reaction. 100 mu M of 13-cis retinoic acid strongly inhibited the activity of UGT1A6 (p < 0.01) and UGT2B7 (p < 0.001). Furthermore, the inhibition kinetic behavior of 13-cis retinoic acid on UGT1A6 and UGT2B7 was determined. 13-cis retinoic acid exhibited concentration- dependent inhibition on the activity towards both UGT1A6 and UGT2B7. The intersection point was located in the horizontal axis and vertical axis for the inhibition of 13-cis retinoic acid on UGT1A6 and UGT2B7, respectively. The fitting equation for the inhibition of 13-cis retinoic acid towards UGT1A6 and UGT2B7 was calculated to be y = 0.16x+5.1 and y = 12.0x + 519.5 for the inhibition of 13-cis retinoic acid towards UGT1A6 and UGT2B7, respectively. Based on these equations, the inhibition kinetic parameters (Ki) were calculated to be 31.9 and 43.3 mu M for UGT1A6 and UGT2B7, respectively. In vitro-in vivo extrapolation (IVIVE) results showed that the thresholds of 13-cis retinoic acid for the inhibition of UGT1A6 and UGT2B7 were calculated to be 31.9 and 43.3 mu M, respectively. In conclusion, 13-cis retinoid acid strongly inhibited the activity of UGT1A6 and UGT2B7, which might increase the exposure of co-administered drugs mainly undergoing UGT1A6 and UGT2B7-catalyzed glucuronidation.