Abi inhibits glucuronidation of adrenal precursors (DHEA and A5-diol) and potent androgens (Testo and DHT)
| Testo-G | DHT-G | DHEA-G | A5-diol-3G | A5-diol-17G | |
|---|---|---|---|---|---|
| Ki (μM) for Abia | |||||
| HLM | 0.24 ± 0.05 | 0.49 ± 0.13 | 1.01 ± 0.36 | 0.90 ± 0.57 | 0.62 ± 0.52 |
| UGT1A4 | n.d. | 1.18 ± 0.19 | 0.41 ± 0.10 | 0.50 ± 0.10 | 0.61 ± 0.10 |
| UGT2B15 | 3.19 ± 3.74 | — | — | — | — |
| UGT2B17 | 0.73 ± 0.53 | — | — | — | — |
| LNCaPb | 0.10 ± 0.04 | — | — | — | — |
L, liver; n.d., not detected because UGT1A4 leads to minor formation of Testo-G; P, prostate; —, not determined.
↵aKi values were derived from experiments using three concentrations of Abi (5, 25, 200 μM) and three concentrations of Testo, DHT, DHEA, and A5-diol (5, 25, 200 μM). For assays using UGT2B15, UGT2B17, and LNCaP cells, we used lower concentrations of Abi (0.1, 1, 5 μM) and testosterone (1, 5, 25 μM). Results are expressed with mean ± S.D. of triplicate determinations of at least two independent experiments. Inhibition of steroid glucuronidation by D4A and 5α-Abi is presented in Supplemental Fig. 6, and compared with Abi for HLM and UGT1A4. These graphical representations (Fig. 6; Supplemental Fig. 6) only illustrate percentage of inhibition observed in assays using 5 μM androgen in the presence of 0, 2, and 200 μM Abi. Inhibition models observed were mixed.
↵b LNCaP cells are androgen-sensitive human prostate adenocarcinoma cells that express several UGTs, namely UGT2B15, UGT2B17, and UGT2B28.