2-methoxyestradiol (2-ME₂) sulfation: Possible metabolic pathway

2-ME₂ is an endogenous estrogen metabolite that inhibits the proliferation of breast and other human cancer cell lines. 2-ME₂ also has potent anti-angiogenic and anti-tubulin properties, and it may inhibit estrogen-induced carcinogenesis in the mammary gland. We set out to test the hypothesis that 2-ME₂ might be a substrate for sulfate conjugation and, therefore, that individual variations in the sulfation of 2-ME₂ might contribute to individual differences in its metabolism, pharmacokinetics and therapeutic efficacy. As a first step, we tested 2-ME₂ as a substrate for 1 human sulfotransferase (SULT) isoforms - as well as all of the common allozymes for SULT1A1 and 1A2. Substrate kinetic studies were conducted in two stages - starting with concentrations over 5 orders of magnitude, followed by determination of K_m values over a narrow concentration range. 2-ME₂ was a sulfate acceptor substrate for SULT1A1* 1, *2, *3; 1A2*1, *2, *3; 1A3; 1E1; 2A1; 2B1a and 2B1b, with apparent K_m values of 2.5, 5.2, 1.6; 4.2, 111, 5.3; 91; 0.067; 8.3; 4.1 and 4.1 μM, respectively. These results suggest that individual pharmacogenetic variation in sulfate conjugation might contribute to individual differences in 2-ME₂ pharmacokinetics and therapeutic effect.