Sulfation of tibolone metabolites by human postmenopausal liver and small intestinal sulfotransferases (SULTs)☆

Sulfation is a major pathway in humans for the biotransformation of steroid hormones and structurally related therapeutic agents. Tibolone is a synthetic steroid used for the treatment for climacteric symptoms and postmenopausal osteoporosis. Sulfation inactivates the hydroxylated metabolites, 3α-hydroxytibolone (3α-OH-tibolone) and 3β-hydroxytibolone (3β-OH-tibolone), and contributes to the regulation of tissue responses to tibolone. We detected SULT1A1, SULT1A3, SULT1E1 and SULT2A1 mRNA expression by RT-PCR in postmenopausal liver and small intestine. Liver pool (n=5) SULT activities measured with tibolone substrates reflected COS-1 expressed SULT2A1 and SULT1E1 activities. Liver SULT2A1 activity (1.8±0.3units/mg protein, n=8, mean±SEM), and activities with 3α-OH-tibolone (0.6±0.1, n=8) and 3β-OH-tibolone (0.9±0.2, n=8) were higher than SULT1E1 activities (<0.05, n=10). SULT1E1 activities were low or not detected in many samples. Mean small intestinal activities were 0.03±0.01 with 3α-OH-tibolone and 0.04±0.01 with 3β-OH-tibolone (n=3). In conclusion, SULT2A1 is the major endogenous enzyme responsible for sulfation of the tibolone metabolites in human postmenopausal tissues. The results support the occurrence of pre-receptor enzymatic regulation of hydroxytibolone metabolites and prompt further investigation of the tissue-selective regulation of tibolone effects.