Sulfotransferase (SULT) 1A1 is the major drug/xenobiotic-conjugating SULT isoform in human liver because of its broad substrate reactivity and high expression level. SULT1A1 sulfates estrogens with low micromolar Km values consistent with its affinity for sulfation of many small phenolic compounds. Binding studies showed the unexpected ability of 17α- ethinylestradiol (EE2) to bind and inhibit SULT1A1 activity toward p-nitrophenol and β-naphthol at low nanomolar concentrations, whereas EE2 was not sulfated until significantly higher concentrations were reached. EE2 had a Ki of 10 nM for inhibiting p-nitrophenol and β-naphthol sulfation and inhibited 17β-estradiol (E2) sulfation in intact human MCF-7 breast cancer cells with a Ki of 19 nM. In contrast, the K m for EE2 sulfation by SULT1A1 was 700 nM. The Kd for EE2 binding of pure SULT1A1 was 0.5 ± 0.15 μM; however, the Kd for EE2 binding to the SULT1A1-PAP complex was >100-fold lower (4.3 ± 1.7 nM). The Kdfor E2 binding to SULT1A1 changed from 2.3 ± 0.9 to 1.2 ± 0.56 μM in the presence of PAP. Docking studies with E2 indicate that E2 binds in a competent orientation in the resolved structure of SULT1A1 in the both presence and absence of 3′-phosphoadenosine 5′-phosphosulfate (PAPS). However, EE2 binds in a catalytically competent orientation in the absence of PAPS but in a noncompetent orientation via formation of a charge interaction with Tyr108 if PAPS is bound first. In conclusion, EE2 is a potent inhibitor, but not a substrate, of SULT1A1 at low nanomolar concentrations, indicating the possibility of drug-drug interactions during contraceptive therapy.
ASJC Scopus subject areas
- Pharmaceutical Science