title: Dehydroepiandrosterone formation is independent of cytochrome P450 17alpha-hydroxylase/17, 20 lyase activity in the mouse brain.
abstract: Cytochrome P450 17alpha-hydroxylase/17, 20 lyase (CYP17) is a microsomal enzyme reported to have two distinct catalytic activities, 17alpha-hydroxylase and 17, 20 lyase, that are essential for the biosynthesis of peripheral androgens such as dehydroepiandrosterone (DHEA). Paradoxically, DHEA is present and plays a role in learning and memory in the adult rodent brain, while CYP17 activity and protein are undetectable. To determine if CYP17 is required for DHEA formation and function in the adult rodent brain, we generated CYP17 chimeric mice that had reduced circulating testosterone levels. There were no detectable differences in cognitive spatial learning between CYP17 chimeric and wild-type mice. In addition, while CYP17 mRNA levels were reduced in CYP17 chimeric compared to wild-type mouse brain, the levels of brain DHEA levels were comparable. To determine if adult brain DHEA is formed by an alternative Fe(2+)-dependent pathway, brain microsomes were isolated from wild-type and CYP17 chimeric mice and treated with FeSO(4). Fe(2+) caused comparable levels of DHEA production by both wild-type and CYP17 chimeric mouse brain microsomes; DHEA production was not reduced by a CYP17 inhibitor. Taken together these in vivo studies suggest that in the adult mouse brain DHEA is formed via a Fe(2+)-sensitive CYP17-independent pathway.
authors.affiliation: Department of Biochemistry & Molecular and Cellular Biology, Washington, DC 20057, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Ana
authors.initials: A
authors.lastname: Pocivavsek
authors.forename: Vassilios
authors.initials: V
authors.lastname: Papadopoulos
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000201:enzymology*; D002678:Chimera / Q000033:anatomy & histology / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000096:biosynthesis*; D005296:Ferrous Compounds / Q000378:metabolism; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000097:blood
chemical_list: D005296:Ferrous Compounds; C020748:ferrous sulfate; D013739:Testosterone; D003687:Dehydroepiandrosterone; D013254:Steroid 17-alpha-Hydroxylase