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, 3alpha-hydroxytibolone (3alpha-OH-tibolone) and 3beta-hydroxytibolone (3beta-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 +/- 0.3 units/mg protein, n = 8, mean +/- SEM), and activities with 3alpha-OH-tibolone (0.6 +/- 0.1, n = 8) and 3beta-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 3alpha-OH-tibolone and 0.04 +/- 0.01 with 3beta-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.
Wang
Min
M
Section of Endocrinology, Veterans Affairs Medical Center, Creighton University Medical Center, Omaha, NE 68105, USA.
Ebmeier
Christopher C
CC
Olin
John R
JR
Anderson
Robert J
RJ
D002851:Chromatography, High Pressure Liquid; D020869:Gene Expression Profiling; D006801:Humans; D007421:Intestine, Small / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D008099:Liver / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology; D009652:Norpregnenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010724:Phosphoadenosine Phosphosulfate / Q000494:pharmacology; D017698:Postmenopause; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012965:Sodium Chloride / Q000494:pharmacology; D015238:Sulfotransferases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013696:Temperature
C485705:3-hydroxytibolone; D009596:Nitrophenols; D009652:Norpregnenes; D012333:RNA, Messenger; D012965:Sodium Chloride; D010724:Phosphoadenosine Phosphosulfate; C015802:2,6-dichloro-4-nitrophenol; D015238:Sulfotransferases; C027385:tibolone