Androstanediol glucuronide production in human liver, prostate, and skin. Evidence for the importance of the liver in 5 alpha-reduced androgen metabolism.

Abstract

Androstanediol glucuronide (Adiol G) has been reported to be a marker of peripheral androgen metabolism and action. It consists of two isomers, Adiol 3-G and Adiol 17-G. Adiol G is formed from unconjugated precursors by the enzyme glucuronyl transferase. To determine the likely source of Adiol G formation in man, we developed a glucuronyl transferase assay and measured the activity of this enzyme in human liver, abdominal and scalp skin, and prostate. In human liver, glucuronyl transferase activity was linear with respect to time (up to 120 min) and tissue concentration (up to 1 mg/ml). Apparent Michaelis-Menten constant Km (micromolar) and maximum velocity (Vmax) (picomoles per mg/30 min) were 5.6 and 140 for dihydrotestosterone, 8.9 and 1300 for androstanediol, and 3.1 and 46 for androsterone, respectively. Conversion of androstanediol to Adiol G (/0.5 mg tissue.30 min) was 5.8-13.2%. Over 80% of the Adiol G formed in human liver was Adiol 17-G, similar to what has been previously found in human serum. Glucuronyl transferase activity was present at low levels in human prostate (conversion of androstanediol to Adiol G was 0.04-4.6%/50 mg tissue.120 min). Analogous conversion rates (/50 mg tissue.120 min) for human scalp skin were 0.2-0.4% and for human abdominal skin were 0.07-0.14%. Although dihydrotestosterone may be converted to androstanediol in peripheral tissues such as skin and prostate, our results suggest that the principal site of androgen conjugation to glucuronic acid is the liver. The present results cast doubt upon the role of androstanediol glucuronide as a specific marker of cutaneous androgen metabolism.

UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells

“…As previously demonstrated in LNCaP cells, androgens are also capable of down-regulating UGT2B15 expression in human normal prostate cells in culture, suggesting that low glucuronidation activity may be generally present in the prostate (17). Significant levels of DHT in the human prostate have been previously reported by several groups, whereas the presence of androgen glucuronides has also been detected in addition to the androgen-conjugating enzyme transcripts and proteins (5,12,19,20,(52)(53)(54)(55). Recently, Vandenput et al (18) have demonstrated that, contrary to several other steroids, namely, dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone, and androstenedione, the serum levels of 3␣-DIOL-17G, a metabolite of DHT, is significantly associated with prostate volume, suggesting that UGT2B enzymes in the prostate secrete this metabolite into circulation.…”

Androgen activity, ischaemic heart disease and risk factors among men in NHANES III

“…However, that does not seem biologically plausible . AAG is partly metabolized in the liver . AAG could largely be a marker of liver function rather than of androgen activity.…”

Isolation and Characterization of a Novel cDNA Encoding a Human UDP-Glucuronosyltransferase Active on C19 Steroids

“…Previously, glucuronidation of androgens in human extrahepatic tissues such as the prostate was examined but yielded conflicting results due to the extremely low level of steroid UGT activity in the prostate as compared with the liver (49). However, the measurement of UGT activities in these studies may be difficult to interpret due to the labile nature of human UGT enzymes during preparation of tissue samples (4).…”