title: In Vitro Inhibition of Human UDP-Glucuronosyl-Transferase (UGT) Isoforms by Astaxanthin, β-Cryptoxanthin, Canthaxanthin, Lutein, and Zeaxanthin: Prediction of in Vivo Dietary Supplement-Drug Interactions.
abstract: Despite the widespread use of the five major xanthophylls astaxanthin, β-cryptoxanthin, canthaxanthin, lutein, and zeaxanthin as dietary supplements, there have been no studies regarding their inhibitory effects on hepatic UDP-glucuronosyltransferases (UGTs). Here, we evaluated the inhibitory potential of these xanthophylls on the seven major human hepatic UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) in vitro by LC-MS/MS using specific marker reactions in human liver microsomes (except UGT2B15) or recombinant supersomes (UGT2B15). We also predicted potential dietary supplement-drug interactions for β-cryptoxanthin via UGT1A1 inhibition. We demonstrated that astaxanthin and zeaxanthin showed no apparent inhibition, while the remaining xanthophylls showed only weak inhibitory effects on the seven UGTs. β-Cryptoxanthin mildly inhibited UGT1A1, UGT1A3, and UGT1A4, with IC50 values of 18.8 ± 2.07, 28.3 ± 4.40 and 34.9 ± 5.98 μM, respectively. Canthaxanthin weakly inhibited UGT1A1 and UGT1A3, with IC50 values of 38.5 ± 4.65 and 41.2 ± 3.14 μM, respectively; and lutein inhibited UGT1A1 and UGT1A4, with IC50 values of 45.5 ± 4.01 and 28.7 ± 3.79 μM, respectively. Among the tested xanthophyll-UGT pairs, β-cryptoxanthin showed the strongest competitive inhibition of UGT1A1 (Ki, 12.2 ± 0.985 μM). In addition, we predicted the risk of UGT1A1 inhibition in vivo using the reported maximum plasma concentration after oral administration of β-cryptoxanthin in humans. Our data suggests that these xanthophylls are unlikely to cause dietary supplement-drug interactions mediated by inhibition of the hepatic UGTs. These findings provide useful information for the safe clinical use of the tested xanthophylls.
authors.affiliation: College of Pharmacy, Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea. cathy8521@hotmail.com.
authors.forename: Yu Fen
authors.initials: YF
authors.lastname: Zheng
authors.affiliation: College of Pharmacy, Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea. sunny08@catholic.ac.kr.
authors.forename: Jee Sun
authors.initials: JS
authors.lastname: Min
authors.affiliation: College of Pharmacy, Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea. doyun325@catholic.ac.kr.
authors.forename: Doyun
authors.initials: D
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea. sacramentou@naver.com.
authors.forename: Jung Bae
authors.initials: JB
authors.lastname: Park
authors.affiliation: Department of Biotechnology, The Catholic University of Korea, Bucheon 14662, Korea. choisw@catholic.ac.kr.
authors.forename: Sung-Wook
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Department of Biotechnology, The Catholic University of Korea, Bucheon 14662, Korea. eslee@catholic.ac.kr.
authors.forename: Eun Seong
authors.initials: ES
authors.lastname: Lee
authors.affiliation: Department of Biotechnology, The Catholic University of Korea, Bucheon 14662, Korea. kna6997@catholic.ac.kr.
authors.forename: Kun
authors.initials: K
authors.lastname: Na
authors.affiliation: College of Pharmacy, Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea. baesk@catholic.ac.kr.
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Bae
mesh_terms: D000072743:Beta-Cryptoxanthin / Q000494:pharmacology*; D016644:Canthaxanthin / Q000494:pharmacology*; D019587:Dietary Supplements; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes; D014975:Lutein / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000201:enzymology; D024341:Xanthophylls / Q000494:pharmacology; D065146:Zeaxanthins / Q000494:pharmacology*
chemical_list: D000072743:Beta-Cryptoxanthin; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D024341:Xanthophylls; D065146:Zeaxanthins; D016644:Canthaxanthin; C005948:astaxanthine; D014453:Glucuronosyltransferase; D014975:Lutein
keywords: in vitro UGTs inhibition; in vitro-in vivo extrapolation; xanthophylls; β-cryptoxanthin