Abstract
Simple SummaryHormone metabolism can vary from one species to another. In humans, specific UDP-glucuronosyltransferase (UGT) enzymes transform androgens (the male hormones) into glucuronide derivatives, which are easier to eliminate. Whether a similar mechanism also takes place in mice has never been ascertained. This study aimed at addressing this question. Organs and pure Ugt2b enzymes from mice were assayed for their ability to transform several androgens into their glucuronide derivatives. Results show that, as in humans, both murine organs and enzymes are reactive with androgen molecules, and glucuronide derivatives are formed with substrate-, organ- and enzyme-specific manner. In conclusion, these observations revealed that glucuronosyltransferase enzymes from mice works in a similar manner as their human counterparts.Glucuronidation, catalyzed by UDP-glucuronosyltransferase UGT2B enzymes, is a major inactivating and elimination pathway for androgen hormones in humans. Whether Ugt2b enzymes from mice are also reactive with these hormones have never been investigated. The present study aimed at evaluating the capability of murine tissues and Ugt2b enzymes to glucuronidated androgens. The 7 murine Ugt2b (Ugt2b1, 2b5, 2b34, 2b35, 2b36, 2b37 and 2b38) enzymes were cloned and stably expressed into HEK293 cells. In vitro glucuronidation assays were performed with microsomal proteins or homogenates from mice tissues (liver, kidney, intestine, adipose, testis, prostate, epididymis, bulbo, seminal vesicle, mammary glands, uterus, and ovary) and from Ugt2b-HEK293 cells. Male and female livers, as well as male kidneys, are the major sites for androgen glucuronidation in mice. The male liver is highly efficient at glucuronidation of dihydrotestosterone (DHT) and testosterone and is enriched in Ugt2b1 and 2b5 enzymes. Androsterone and 3α-Diol are conjugated in the male kidney through an Ugt2b37-dependent process. Interestingly, castration partially abolished hepatic Ugt2b1 expression and activity, while Ugt2b37 was totally repressed. DHT injection partially corrected these changes. In conclusion, these observations revealed the substrate- and tissue-specific manner in which murine Ugt2b enzymes conjugate androgens. They also evidence how androgens modulate their own glucuronide conjugation in mice.
Highlights
UDP-glucuronosyltransferase (UGT) enzymes catalyze the glucuronidation reaction, a conjugation process corresponding to the addition of the glucuronic moiety from the UDPglucuronic acid (UDPGA) co-substrate to various endogenous and exogenous molecules [1]
The capability of murine tissues to convert androgens into glucuronides was evaluated using in vitro glucuronidation assays performed in the presence of 100 μM of testosterone, DHT, ADT or 3α-Diol (Figure 1A,B)
To evaluate whether androgens control their own glucuronidation in mice, we investigated whether DHT affects the expression and activity of the Ugt2b1 and Ugt2b37 enzyme in male mice liver and kidney
Summary
UDP-glucuronosyltransferase (UGT) enzymes catalyze the glucuronidation reaction, a conjugation process corresponding to the addition of the glucuronic moiety from the UDPglucuronic acid (UDPGA) co-substrate to various endogenous and exogenous molecules [1] This reaction converts hydrophobic aglycons into highly polar molecules, and facilitates their removal from the human body in bile and urine [2]. Seven human UGT2Bs have been identified (UGT2B4, 2B7, 2B10, 2B11, 2B15, 2B17, and 2B28) and are encoded by different genes, all clustered on chromosome 4q13-4q21.1 [4,5] These enzymes are expressed in numerous tissues, including the liver, as well as steroid target tissues, such as the prostate, breast, skin, testis, and adipose tissue [3]. Seven Ugt2b enzymes (Ugt2b1, 2b5, 2b34, 2b35, 2b36, 2b37, and 2b38) have been identified [6,7]
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