Comparative biosynthetic pathway of androstenol and androgens

It has been shown recently that androstenol and androstanol could modulate gene expression through the nuclear orphan receptors CAR (constitutive andr ostane receptor) and PXR (pregnane X receptor). Although, in the pig, andro stenol is produced in high amounts and is active as a pheromone, its role i n the human is ill defined. Androstenol possesses a structure similar to th at of androgens, with the exception that it does not possess an oxygen at p osition 17 that is crucial for androgenic and estrogenic activity. It has b een shown that human and boar testis homogenates could produce androstenol, but details of the biosynthetic pathway had not yet been elucidated. It ha s also been shown recently that androstenol could modulate the activity of CAR and PXR and the expression of some cytochrome P450 drug-metabolizing en zymes. We wanted to determine the precise biosynthetic pathway of androsten ol and other closely related steroids. Using transformed human embryonic ki dney (HEK-293) cells that stably express 3 beta -hydroxysteroid dehydrogena se, 5 alpha -reductase and 3 alpha -hydroxysteroid dehydrogenase, we have s hown that these enzymes are able to efficiently transform the precursor 5,1 6-androstadien-3 beta -ol into androstenol. We thus provided evidence that androstenol, We thus provided evidence that androstenol, the ligand for CAR and PXR, is produced by the biosynthetic pathway of sex steroids. (C) 2001 Elsevier Science Ltd. All rights reserved.