Table 1.
Experimentally determined kinetic parameters for UGT1A9-mediated glucuronidation of 145 compounds, including 2 catecins (No.1–2), 5 chalcones (No.3–7), 1 chromone (No.8), 6 courmarins (No.9–14), 3 curcumins (No.15–17), 6 aromatic hydrocarbons (No.18–23), 4 flavanones (No.24–27), 31 flavones (No.28–58), 36 flavonols (No.59–94), 3 hydroxycinnamic acids (No.95–97), 11 isoflavones (No.98–108), 27 phenols (No.109–135), and 7 other compounds (No.136–145). The chemical structures (including the SMILES codes) of all compounds are shown in Fig.S1 (Supporting Information). The site of glucuronidation is indicated in the parenthesis. For a compound with multiple glucuronides generated, a lower-case letter is appended for a distinction.
| No. | Name | Km | Vmax | CLint (Vmax/Km) | Log (CLint) | Log (CLint) | Log (CLint) |
|---|---|---|---|---|---|---|---|
| μM | pmol/mg/min | μl/mg/min | (Actual) | (CoMFA) | (CoMSIA) | ||
| 1.a | (−)-Epigallocatechingallate (3′-OH) | 18.7 | 2955 | 158 | 2.20 | 2.32 | 2.42 |
| 1.b | (−)-Epigallocatechingallate (4″-OH) | 15.3 | 9984 | 646 | 2.81 | 2.72 | 3.36 |
| 2 | (−)-Epigallocatechin(3′-OH) | 135 | 5130 | 38 | 1.58 | 1.40 | 1.90 |
| 3 | 2-Hydroxychalcone$ | 0.23 | 552 | 2400 | 3.38 | 3.83 | 3.36 |
| 4 | 4-Hydroxychalcone$ | 1.62 | 54.8 | 34 | 1.53 | 1.68 | 1.32 |
| 5 | 2′-Hydroxychalcone$ | 0.77 | 1008 | 1309 | 3.12 | 2.80 | 2.40 |
| 6 | 4′-Hydroxychalcone$ | 1.72 | 339 | 197 | 2.29 | 1.95 | 1.97 |
| 7.a | Phloretin (2′-OH)$ | 0.63 | 467 | 741 | 2.87 | 2.88 | 2.64 |
| 7.b | Phloretin (4′-OH)$ | 0.43 | 636 | 1479 | 3.17 | 3.21 | 3.14 |
| 8 | 7-Hydroxychromone | 82.8 | 668 | 8 | 0.91 | 1.37 | 1.62 |
| 9 | 3,4-Diphenyl-7-hydroxycoumarin | 3.37 | 137 | 41 | 1.61 | 1.53 | 1.46 |
| 10 | 4-Methylumbelliferone | 12 | 3653 | 304 | 2.48 | 2.43 | 2.06 |
| 11 | 4-Hydroxy-6-methylcoumarin | 57.8 | 225 | 4 | 0.59 | 1.06 | 0.84 |
| 12 | 6-Hydroxy-7-methoxyl-4-phenylcoumarin | 312 | 3744 | 12 | 1.07 | 1.04 | 1.69 |
| 13 | 8-Hydroxywarfarin | 369 | 9229 | 25 | 1.40 | 1.69 | 1.67 |
| 14 | Scopoletin | 5.53 | 1064 | 192 | 2.28 | 2.60 | 2.56 |
| 15 | Curcumin | 35.4 | 1958 | 55 | 1.74 | 1.59 | 1.60 |
| 16 | Demethoxycurcumin | 18.6 | 258 | 14 | 1.14 | 1.37 | 1.16 |
| 17 | Bisdemethoxycurcumin * | 257 | 2070 | 8 | 0.90 | 1.04 | 0.68 |
| 18 | Emodin | 2.87 | 2928 | 1020 | 3.01 | 3.10 | 3.05 |
| 19 | Endoxifen * | 316 | 2086 | 6.6 | 0.82 | 1.97 | 1.01 |
| 20 | Enterolactone (3-OH) | 57.4 | 5292 | 92 | 1.96 | 1.95 | 2.04 |
| 21 | Naphthol$ | 0.25 | 72.1 | 288 | 2.46 | 1.89 | 1.55 |
| 22 | Raloxifene (6-OH) | 1.93 | 39.3 | 20 | 1.31 | 1.15 | 1.06 |
| 23.a | Tyrphostin B42 (3-OH) | 3.60 | 3677 | 1020 | 3.01 | 3.02 | 3.16 |
| 23.b | Tyrphostin B42 (4-OH) * | 14.5 | 2008 | 138 | 2.14 | 2.27 | 2.63 |
| 24 | 7-Hydroxyflavanone * | 3.34 | 5001 | 1497 | 3.18 | 2.88 | 2.58 |
| 25 | 4′-Hydroxy-3-methoxyflavanone | 83.4 | 1687 | 20 | 1.31 | 1.29 | 1.39 |
| 26.a | Hesperetin (3′-OH) | 4.29 | 4192 | 977 | 2.99 | 2.99 | 3.31 |
| 26.b | Hesperetin (7-OH) | 6.00 | 2444 | 407 | 2.61 | 2.45 | 2.49 |
| 27 | Narigenin (7-OH) | 3.34 | 5001 | 1497 | 3.18 | 3.35 | 2.98 |
| 28 | 2′-Hydroxyflavone | 0.40 | 74.4 | 186 | 2.27 | 2.44 | 2.26 |
| 29 | 3,4′-Dimethoxy-5,7,3′-trihydroxyflavone (7-OH) | 1.64 | 7494 | 4570 | 3.66 | 3.43 | 3.43 |
| 30 | 3′-Benzyloxy-5,7-dihydroxy-3,4′-dimethoxyflavone (7-OH) | 1.25 | 2079 | 1663 | 3.22 | 3.25 | 3.22 |
| 31 | 3′-Hydroxyflavone | 2.02 | 926 | 458 | 2.66 | 2.66 | 2.63 |
| 32 | 4′-Hydroxyflavone | 1.46 | 98.7 | 67.6 | 1.83 | 1.83 | 2.11 |
| 33 | 5,7-Dihydroxy-3′,4′,5′-trimethoxyflavone (7-OH) | 0.45 | 382 | 849 | 2.93 | 3.25 | 2.84 |
| 34 | 5-Hydroxyflavone | 0.96 | 118 | 123 | 2.09 | 2.09 | 2.77 |
| 35 | 6,3′,4′-Trihydroxyflavone (3′-OH)# | 1.87 | 6470 | 3450 | 3.54 | 2.93 | 2.86 |
| 36 | 6,7,3′-Trihydroxflavone (7-OH) | 3.01 | 2333 | 775 | 2.89 | 3.05 | 3.14 |
| 37 | 6,7-Dihydroxyflavone (7-OH) | 4.49 | 4090 | 910 | 2.96 | 3.07 | 3.18 |
| 38 | 6-Hydroxyflavone | 2.27 | 76.1 | 34 | 1.53 | 1.30 | 1.64 |
| 39 | 6-Methoxyluteolin (7-OH) | 1.15 | 1902 | 1654 | 3.22 | 3.28 | 3.18 |
| 40 | 5,7,2′-Trihydroxyflavone (7-OH) * | 0.23 | 862 | 3748 | 3.57 | 3.44 | 3.39 |
| 41.a | 7,3′,4′-Trihydroxyflavone (3′-OH) | 2.45 | 2921 | 1192 | 3.08 | 3.23 | 2.92 |
| 41.b | 7,3′,4′-Trihydroxyflavone (4′-OH) | 2.44 | 744 | 305 | 2.48 | 2.38 | 2.74 |
| 41.c | 7,3′,4′-Trihydroxyflavone (7-OH) | 6.38 | 820 | 128 | 2.11 | 2.70 | 2.75 |
| 42 | 7,2′-Dihydroxyflavone (7-OH)* | 0.65 | 381 | 586 | 2.77 | 2.74 | 2.94 |
| 43 | 7,3′-Dihydroxyflavone (7-OH) | 29.6 | 16166 | 546 | 2.74 | 2.85 | 2.86 |
| 44 | 7-Hydroxy-2′-methoxyflavone | 2.21 | 2228 | 1008 | 3.00 | 3.04 | 2.82 |
| 45 | 7-Hydroxy-3-methylflavone | 1.46 | 2929 | 2006 | 3.30 | 3.19 | 2.83 |
| 46 | 7-Hydroxy-3′-methoxyflavone* | 25.3 | 132 | 5 | 1.02 | 2.81 | 2.80 |
| 47 | 7-Hydroxy-4′-methoxyflavone | 3.37 | 764 | 227 | 2.36 | 3.00 | 3.24 |
| 48 | 7-Hydoxy-5-methylflavone | 0.94 | 5369 | 5712 | 3.76 | 3.34 | 3.03 |
| 49 | 7-Hydroxyflavone | 3.59 | 4895 | 1364 | 3.13 | 2.88 | 2.90 |
| 50 | Apigenin (7-OH) | 1.93 | 3289 | 1704 | 3.23 | 2.96 | 3.24 |
| 51 | Baicalein (OH)# | 0.70 | 5310 | 7586 | 3.88 | 3.37 | 3.64 |
| 52 | Chrysin (7-OH) | 0.25 | 4537 | 18148 | 3.96 | 3.56 | 3.34 |
| 53 | Chrysoeriol (7-OH) | 0.91 | 2765 | 3038 | 3.48 | 3.16 | 3.09 |
| 54 | Diosmetin (7-OH) | 0.56 | 5361 | 9573 | 3.41 | 2.63 | 2.99 |
| 55 | Flavopiridol (7-OH) | 37.5 | 219 | 5.8 | 0.77 | 0.57 | 1.02 |
| 56.a | Luteolin (3′-OH) | 0.17 | 660 | 3870 | 3.58 | 3.56 | 3.08 |
| 56.b | Luteolin (7-OH) | 0.33 | 700 | 2100 | 3.32 | 3.38 | 3.20 |
| 57 | OroxylinA (7-OH) | 2.38 | 2060 | 866 | 2.94 | 3.46 | 3.32 |
| 58 | Wogonin (7-OH) | 1.27 | 5070 | 3992 | 3.60 | 3.98 | 3.63 |
| 59 | 3,2′-Dihydroxyflavone (3-OH) | 0.67 | 52 | 78 | 1.89 | 2.68 | 3.34 |
| 60 | 3,3′-Dihydroxyflavone (3-OH)* | 0.11 | 3100 | 29000 | 4.44 | 4.31 | 4.30 |
| 61 | 3,5-Dihydroxyflavone (3-OH)* | 0.25 | 1900 | 7400 | 3.87 | 4.05 | 3.88 |
| 62 | 3,6,4′-Trihydroxyflavone (3-OH)* | 0.31 | 6800 | 22000 | 4.34 | 4.31 | 3.97 |
| 63 | 3,3′,4′-Trihydroxyflavone (3-OH) | 0.10 | 2200 | 22000 | 4.34 | 4.21 | 3.92 |
| 64 | 3,4′-Dihydroxyfavone (3-OH) | 0.13 | 1800 | 14000 | 4.14 | 3.89 | 3.77 |
| 65 | 3,6-Dihydroxyfavone (3-OH) | 0.62 | 13000 | 21000 | 4.32 | 4.42 | 4.34 |
| 66 | 3-Hydroxy-6-methylflavone * | 0.062 | 6750 | 110000 | 5.04 | 4.34 | 4.29 |
| 67.a | 3,7-Dihydroxy-3′,4′,5′-trimethoxyflavone (3-OH) | 0.63 | 2872 | 4551 | 3.66 | 3.67 | 3.70 |
| 67.b | 3,7-Dihydroxy-3′,4′,5′-trimethoxyflavone (7-OH) * | 1.61 | 289 | 180 | 1.00 | 1.15 | 2.17 |
| 68.a | 3,7-Dihydroxyflavone (3-OH)# | 0.22 | 4600 | 21000 | 4.32 | 3.69 | 4.18 |
| 68.b | 3,7-Dihydroxyflavone (7-OH) | 1.50 | 2040 | 1360 | 3.13 | 3.09 | 3.05 |
| 69.a | 3,7-Dihydroxy-3′,4′-dimethoxyflavone (3-OH) | 1.03 | 753 | 731 | 3.16 | 3.48 | 3.79 |
| 69.b | 3,7-Dihydroxy-3′,4′-dimethoxyflavone (7-OH) | 1.16 | 11.6 | 10 | 1.00 | 1.22 | 2.37 |
| 70 | 3,7,3′-Trihydroxyflavone (3-OH) * | 3.37 | 764 | 227 | 2.86 | 4.00 | 4.33 |
| 71 | 3-Hydroxy-2′,3′-dimethoxyflavone | 0.52 | 4400 | 16000 | 3.92 | 3.60 | 3.91 |
| 72 | 3-Hydroxy-2′-methoxyflavone | 0.21 | 3800 | 18000 | 4.25 | 4.10 | 3.47 |
| 73 | 3-Hydroxy-3′-methoxyflavone | 0.063 | 2900 | 46000 | 4.66 | 4.56 | 4.58 |
| 74 | 3-Hydroxy-4′-methoxyflavone | 0.059 | 1900 | 32000 | 4.51 | 4.24 | 4.47 |
| 75 | 3-Hydroxy-5,7-dimethoxyflavone | 0.13 | 3300 | 26000 | 4.40 | 4.35 | 4.59 |
| 76 | 3-Hydroxy-5-methoxyflavone | 0.082 | 1900 | 24000 | 4.36 | 4.56 | 4.46 |
| 77 | 3-Hydroxy-6,4′-dimethoxyflavone | 0.043 | 2200 | 51000 | 4.71 | 4.97 | 5.05 |
| 78 | 3-Hydroxy-6-methoxyflavone | 0.074 | 5400 | 73000 | 4.86 | 4.97 | 4.79 |
| 79 | 3-Hydroxy-7,4′-dimethoxyflavone | 0.19 | 8700 | 46000 | 4.66 | 4.47 | 4.60 |
| 80 | 3-Hydroxy-7-methoxyflavone | 0.27 | 10000 | 37000 | 4.57 | 4.36 | 4.28 |
| 81 | 3-Hydroxyflavone | 0.30 | 2100 | 7000 | 3.84 | 4.01 | 4.15 |
| 82 | 3-Hydroxy-6-methyl-3′,4′-methylenedioxyflavone | 0.066 | 6000 | 91000 | 4.96 | 4.82 | 4.63 |
| 83 | Datiscetin (3-OH) * | 2.46 | 246 | 100 | 2.00 | 2.42 | 3.10 |
| 84.a | Fisetin (3-OH) | 0.63 | 1500 | 2300 | 3.38 | 3.90 | 3.95 |
| 84.b | Fisetin (3′-OH) | 0.74 | 2620 | 3520 | 3.55 | 3.37 | 3.33 |
| 84.c | Fisetin (4′-OH) | 0.52 | 1620 | 3090 | 3.49 | 3.63 | 3.54 |
| 85.a | Galangin (3-OH)# | 0.68 | 7400 | 11000 | 4.04 | 3.71 | 3.91 |
| 85.b | Galangin (7-OH) | 0.54 | 2560 | 4740 | 3.68 | 3.77 | 3.50 |
| 86 | Geraldol (3-OH) | 1.47 | 5885 | 4003 | 3.60 | 3.89 | 3.76 |
| 87 | Isorhamnetin (3-OH) | 0.32 | 12000 | 38000 | 4.59 | 4.13 | 3.49 |
| 88.a | Kaempferol (3-OH) | 0.32 | 1900 | 6000 | 3.78 | 3.60 | 3.54 |
| 88.b | Kaempferol (7-OH) * | 3.87 | 870 | 220 | 2.34 | 3.36 | 3.41 |
| 89 | Morin (3-OH) | 0.68 | 40 | 60 | 1.77 | 2.33 | 2.73 |
| 90.a | Myricetin (3-OH) | 0.61 | 490 | 800 | 2.90 | 3.33 | 3.39 |
| 90.b | Myricetin (3′-OH)# | 0.67 | 1530 | 2290 | 3.36 | 3.25 | 3.73 |
| 90.c | Myricetin (4′-OH) | 0.64 | 3170 | 4930 | 3.69 | 3.69 | 3.30 |
| 91.a | Quercetin (3-OH) * | 0.36 | 3300 | 9200 | 3.97 | 3.91 | 3.68 |
| 91.b | Quercetin (3′-OH) | 0.90 | 1880 | 2100 | 3.32 | 3.49 | 3.44 |
| 91.c | Quercetin (7-OH) | 0.85 | 3820 | 4490 | 3.65 | 3.52 | 3.24 |
| 92.a | Resokaempferol (3-OH) | 0.36 | 2600 | 7300 | 3.86 | 3.59 | 3.80 |
| 92.b | Resokaempferol (7-OH) * | 2.67 | 1150 | 430 | 2.63 | 2.67 | 2.94 |
| 93 | Rhamnetin (3-OH) | 0.23 | 10000 | 45000 | 4.65 | 4.34 | 3.84 |
| 94.a | Syringetin (3OH) | 0.98 | 7810 | 7333 | 3.87 | 4.11 | 3.46 |
| 94.b | Syringetin (7OH) | 1.61 | 289 | 178 | 2.26 | 2.05 | 2.88 |
| 95 | Ferulic Acid * | 884 | 372 | 0.4 | 0.30 | 1.50 | 0.09 |
| 96 | Isoferulic Acid | 237 | 15640 | 66 | 1.82 | 1.62 | 1.16 |
| 97.a | Caffeic Acid (3-OH) | 564 | 6204 | 11 | 1.04 | 1.50 | 0.86 |
| 97.b | Caffeic Acid (4-OH) | 1012 | 2024 | 2 | 0.30 | 0.51 | 0.50 |
| 98 | 7-Hydroxy-6-methoxyisoflavone | 3.08 | 1143 | 371 | 2.57 | 2.44 | 2.21 |
| 99 | 8-Hydroxy-7-methoxyisoflavone | 1.42 | 5299 | 3732 | 3.57 | 3.76 | 3.34 |
| 100 | Biochanin A (7-OH) * | 1.13 | 379 | 335 | 2.53 | 2.17 | 1.93 |
| 101 | Daidzein (7-OH) | 14.3 | 1107 | 77 | 1.89 | 2.17 | 1.78 |
| 102 | Dihydrodaidzein (7-OH) | 77.7 | 628 | 8.1 | 0.91 | 0.89 | 0.74 |
| 103 | Equol (7-OH) | 213 | 794 | 3.7 | 0.57 | 0.44 | 0.68 |
| 104 | Formononetin (7-OH) | 4.59 | 139 | 30 | 1.48 | 1.48 | 1.48 |
| 105 | Genistein (7-OH) | 2.09 | 1290 | 617 | 2.79 | 2.96 | 2.23 |
| 106 | Glycitein (7-OH) | 1.47 | 403 | 274 | 2.44 | 2.56 | 2.33 |
| 107 | Maackiain | 3.12 | 234 | 75 | 1.87 | 1.57 | 1.29 |
| 108 | Prunetin (5-OH) | 1.29 | 230 | 178 | 2.25 | 2.20 | 2.42 |
| 109 | 4-Bromophenol *# | 30.9 | 3057 | 99 | 2.00 | 1.53 | 1.49 |
| 110 | 4-n-Butylphenol | 43.1 | 647 | 15 | 1.18 | 1.45 | 1.53 |
| 111 | 4-Chlorophenol | 34.0 | 3230 | 95 | 1.98 | 1.44 | 1.60 |
| 112 | 4-Cyclopentylphenol# | 18.2 | 1083 | 60 | 1.78 | 1.40 | 1.11 |
| 113 | 4-Ethoxyphenol | 454 | 3761 | 8.3 | 0.92 | 1.25 | 1.57 |
| 114 | 4-Ethylphenol *# | 15.8 | 1179 | 75 | 1.87 | 1.45 | 1.39 |
| 115 | 4-Fluorophenol * | 112 | 1680 | 15 | 1.18 | 1.56 | 1.79 |
| 116 | 4-Iodophenol | 20.5 | 3034 | 148 | 1.87 | 1.40 | 1.35 |
| 117 | 4-Isopropylphenol | 36.4 | 2184 | 60 | 1.78 | 1.62 | 1.17 |
| 118 | 4-Methoxyphenol | 154 | 2310 | 15 | 1.18 | 1.01 | 1.41 |
| 119 | 4-Methylphenol | 57.3 | 1433 | 25 | 1.39 | 1.30 | 1.41 |
| 120 | 4-Nitrophenol# | 80.6 | 2902 | 36 | 1.56 | 1.50 | 1.92 |
| 121 | 4-Hydroxyacetophenone | 317 | 4438 | 14 | 1.15 | 1.40 | 1.61 |
| 122 | 4-Hydroxybenzophenone | 35.9 | 2441 | 68 | 1.83 | 1.90 | 1.38 |
| 123 | 4-Phenylphenol | 56.2 | 1236 | 22 | 1.34 | 1.50 | 1.33 |
| 124 | 4-Phenylazophenol | 82.5 | 1155 | 14 | 1.15 | 1.29 | 1.48 |
| 125 | 4-Propoxyphenol | 156 | 1560 | 10 | 1.00 | 1.06 | 1.55 |
| 126 | 4-n-Propylphenol | 47.6 | 1999 | 42 | 1.62 | 1.49 | 1.39 |
| 127 | 4-sec-Butylphenol * | 87.5 | 3237 | 37 | 1.57 | 1.66 | 1.19 |
| 128 | 4-tert-Butylphenol * | 78.4 | 5253 | 67 | 1.83 | 1.90 | 1.47 |
| 129 | Butyl-4-hydroxybenzoate | 84.1 | 2691 | 32 | 1.51 | 1.51 | 1.91 |
| 130 | Ethyl-4-hydroxybenzoate | 74.5 | 3055 | 41 | 1.61 | 1.43 | 1.97 |
| 131 | Eugenol | 25 | 1004 | 40 | 1.60 | 1.80 | 1.95 |
| 132 | Methyl-4-hydroxybenzoate | 101 | 5454 | 54 | 1.73 | 1.61 | 1.98 |
| 133 | Propofol | 26 | 148 | 6 | 0.76 | 0.86 | 1.32 |
| 134 | Propyl-4-hydroxybenzoate | 152 | 4560 | 30 | 1.48 | 1.54 | 2.08 |
| 135 | Bisphenol A | 91.8 | 4420 | 48 | 1.68 | 1.85 | 1.02 |
| 136 | Combretastatin A4# | 4.18 | 9009 | 2155 | 3.33 | 3.34 | 2.88 |
| 137 | Pterostilbene | 35.9 | 40.4 | 1.1 | 0.05 | −0.09 | 0.52 |
| 138 | Resveratrol (3-OH) | 3.09 | 196 | 63 | 1.8 | 2.23 | 2.14 |
| 139 | A-769662 (6-OH) | 0.78 | 10.8 | 14 | 1.14 | 0.89 | 0.62 |
| 140 | Entacapone (3-OH) | 8.64 | 88400 | 10233 | 4.01 | 4.10 | 4.43 |
| 141 | Ezetimibe | 268 | 73.6 | 0.30 | −0.56 | −0.68 | −0.50 |
| 142 | Mycophenolic Acid | 71.5 | 6538 | 91 | 1.96 | 1.99 | 1.92 |
| 143 | Psilocin | 748 | 5984 | 8 | 0.90 | 0.90 | 0.66 |
| 144 | SN-38 | 26.4 | 73.1 | 3 | 0.44 | 0.68 | 0.41 |
| 145 | Tolcapone (3-OH) * | 43.4 | 18100 | 417 | 2.62 | 2.79 | 2.08 |
*
These 25 compounds were used as a test set and not included in the derivation of model equations.
#
Described using the substrate inhibition equation (eq.2). Ksi value is not shown because it is unimportant in calculation of CLint (please see Materials and Methods).
$
Described using a biphasic kinetics model (eq.3). Km1and Vmax1 values are shown in the columns Km and Vmax, respectively. CLint2 value is not shown because it is unimportant in calculation of CLint (please see Materials and Methods).