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.
Highlights
Xanthophylls have been studied for their beneficial effects, including their powerful antioxidant activities and association with lower incidence of chronic diseases [1,2,3,4]
Intake of LU and ZE was associated with decreased age-related macular degeneration risk and less visual impairment [12,13,15]
The difference between human recombinant supersomes and microsomes is that the is former contain single UGT. Enzyme, whereaswhereas the latter all hepatic human liver microsomes that the formera contain a single
Summary
Xanthophylls have been studied for their beneficial effects, including their powerful antioxidant activities and association with lower incidence of chronic diseases [1,2,3,4]. ΒC is mainly found in fruits and vegetables, such as tangerines, green grapes, coriander, parsley, basil, red peppers, and pumpkin, and it has been shown to have antioxidant activity [8,9]. Intake of CA has been associated with a reduced risk of cancer [10,11]. The highest concentrations of LU are found in dark green leafy vegetables, corn, and egg yolks, while ZE is found in corn, orange pepper, oranges, and tangerines [14]. Intake of LU and ZE was associated with decreased age-related macular degeneration risk and less visual impairment [12,13,15]
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