Dehydroepiandrosterone 7-hydroxylase CYP7B: predominant expression in primate hippocampus and reduced expression in Alzheimer's disease.
Neurosteroids such as dehydroepiandrosterone (DHEA), pregnenolone and 17beta-estradiol are synthesized by cytochrome P450s from endogenous cholesterol. We previously reported a new cytochrome P450 enzyme, CYP7B, highly expressed in rat and mouse brain that metabolizes DHEA and related steroids by hydroxylation at the 7alpha position. Such 7-hydroxylation can enhance DHEA bioactivity in vivo. Here we show that the reaction is conserved across mammalian species: in addition to mouse and rat, DHEA hydroxylation activity was present in brain extracts from sheep, marmoset and human. Northern blotting using a human CYP7B complementary deoxyribonucleic acid (cDNA) probe confirmed the presence of CYP7B mRNA in marmoset and human hippocampus; CYP7B mRNA was present in marmoset cerebellum and brainstem, with lower levels in hypothalamus and cortex. In situ hybridization to human brain revealed higher levels of CYP7B mRNA in the hippocampus than in cerebellum, cortex, or other brain regions. We also measured CYP7B expression in Alzheimer's disease (AD). CYP7B mRNA was significantly decreased (approximately 50% decline; P<0.05) in dentate neurons from AD subjects compared with controls. A decline in CYP7B activity may contribute the loss of effects of DHEA with ageing and perhaps to the pathophysiology of AD.
Yau
J L W
JL
Molecular Medicine Centre, Western General Hospital, Edinburgh EH4 2XU, UK. joyce.yau@ed.ac.uk
Rasmuson
S
S
Andrew
R
R
Graham
M
M
Noble
J
J
Olsson
T
T
Fuchs
E
E
Lathe
R
R
Seckl
J R
JR
D000272:Adipates / Q000737:chemistry / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology*; D000818:Animals; D015152:Blotting, Northern; D001921:Brain / Q000033:anatomy & histology / Q000196:embryology; D002144:Callithrix; D016022:Case-Control Studies; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072474:Cytochrome P450 Family 7; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000201:enzymology*; D006801:Humans; D006900:Hydroxylation; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012756:Sheep; D013250:Steroid Hydroxylases / Q000378:metabolism*
D000272:Adipates; D018076:DNA, Complementary; D012333:RNA, Messenger; C013966:dioctyl adipate; D003577:Cytochrome P-450 Enzyme System; D006913:Hydroxysteroid Dehydrogenases; C031932:7 beta-hydroxysteroid dehydrogenase; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C097207:Cyp7b1 protein, mouse; C490784:Cyp7b1 protein, rat