Human Efflux Transport of Testosterone, Epitestosterone and Other Androgen Glucuronides

Erkka Järvinen, Heidi Kidron, Moshe Finel

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Several drug-metabolizing enzymes are known to control androgen homeostasis in humans. UDP-glucuronosyltransferases convert androgens to glucuronide conjugates in the liver and intestine, which enables subsequent elimination of these conjugated androgens via urine. The most important androgen is testosterone, while others are the testosterone metabolites androsterone and etiocholanolone, and the testosterone precursor dehydroepiandrosterone. Epitestosterone is another endogenous androgen, which is included as a crucial marker in urine doping tests. Since glucuronide conjugates are hydrophilic, efflux transporters mediate their excretion from tissues. In this study, we employed the membrane vesicle assay to identify the efflux transporters for glucuronides of androsterone, dehydroepiandrosterone, epitestosterone, etiocholanolone and testosterone. The human hepatic and intestinal transporters MRP2 (ABCC2), MRP3 (ABCC3), MRP4 (ABCC4), BCRP (ABCG2) and MDR1 (ABCB1) were studied in vitro. Of these transporters, only MRP2 and MRP3 transported the androgen glucuronides investigated. In kinetic analyses, MRP3 transported glucuronides of androsterone, epitestosterone and etiocholanolone at low K-m values, between 0.4 and 4 mu M, while the K-m values for glucuronides of testosterone and dehydroepiandrosterone were 14 and 51 pM, respectively. MRP2 transported the glucuronides at lower affinity, as indicated by K-m values over 100 mu M. Interestingly, the MRP2-mediated transport of androsterone and epitestosterone glucuronides was best described by sigmoidal kinetics. The inability of BCRP to transport any of the androgen glucuronides investigated is drastically different from its highly active transport of several estrogen conjugates. Our results explain the transporter-mediated disposition of androgen glucuronides in humans, and shed light on differences between the human efflux transporters MRP2, MRP3, MRP4, BCRP and MDR1.
Original languageEnglish
Article number105518
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume197
Number of pages9
ISSN0960-0760
DOIs
Publication statusPublished - Mar 2020
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 317 Pharmacy
  • 1182 Biochemistry, cell and molecular biology
  • ABCC2
  • ABCC3
  • ABCC4
  • ABCG2
  • ABCB1
  • Androgen
  • URINARY MARKERS
  • HEALTHY-MEN
  • METABOLISM
  • DEHYDROEPIANDROSTERONE
  • PLASMA
  • 4-C-14-TESTOSTERONE
  • CONSEQUENCES
  • ANDROSTERONE
  • CHOLESTEROL
  • DISPOSITION

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