The steroid sulfatase inhibitor COUMATE attenuates rather than enhances access of dehydroepiandrosterone sulfate to the brain in the mouse.
Intraperitoneal injection of adult male mice with the neuroactive steroid dehydroepiandrosterone sulfate (DHEAS) at 1 and 40 mg/kg caused dose-dependent increases in the concentration of both this compound and its corresponding free steroid DHEA in brain within 1 h of injection. Pretreatment of these animals for 24 h with the steroid sulfatase inhibitor COUMATE at a dose (10 mg/kg, p.o.) shown previously to cause almost complete inhibition of this enzyme in liver and brain was expected to increase the amount of the DHEAS dose reaching the brain. Surprisingly however, the increases in brain concentrations of DHEAS and DHEA after injection of DHEAS i.p. were attenuated by pretreatment with COUMATE. The results suggest that the arylsulfamate based steroid sulfatase inhibitors such as COUMATE interfere with the influx of the DHEAS anion into the brain.
Nicolas
Laurent B
LB
Department of Physiology, University College London, Gower Street, London, WC1E 6BT, UK.
Fry
Jonathan P
JP
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D003374:Coumarins / Q000494:pharmacology*; D003687:Dehydroepiandrosterone / Q000378:metabolism; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism* / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*
C100463:4-methylcoumarin 7-O-sulfamate; D003374:Coumarins; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D043266:Steryl-Sulfatase