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J. Biol. Chem., Vol. 276, Issue 26, 23937-23944, June 29, 2001

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Neurosteroid Hydroxylase CYP7B
VIVID REPORTER ACTIVITY IN DENTATE GYRUS OF GENE-TARGETED MICE AND ABOLITION OF A WIDESPREAD PATHWAY OF STEROID AND OXYSTEROL HYDROXYLATION^*

Ken Rose, Adrian Allan^§, Stephan Gauldie, Genevieve Stapleton, Lorraine Dobbie, Karin Dott^¶, Cécile Martin, Ling Wang^§, Eva Hedlund^§, Jonathan R. Seckl^**, Jan-Åke Gustafsson^§**, and Richard Lathe

From the  Centre for Genome Research and Centre for Neuroscience, University of Edinburgh, King's Buildings, Edinburgh EH9 3JQ, United Kingdom, the ^§ Karolinska Institute, 14186 Huddinge, Sweden, ^¶ Transgène SA, 11 Rue de Molsheim, 67000 Strasbourg, France, and the  Molecular Medicine Centre, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom

The major adrenal steroid dehydroepiandrosterone (DHEA) enhances memory and immune function but has no known dedicated receptor; local metabolism may govern its activity. We described a cytochrome P450 expressed in brain and other tissues, CYP7B, that catalyzes the 7-hydroxylation of oxysterols and 3-hydroxysteroids including DHEA. We report here that CYP7B mRNA and 7-hydroxylation activity are widespread in rat tissues. However, steroids related to DHEA are reported to be modified at positions other than 7, exemplified by prominent 6-hydroxylation of 5-androstane-3,17-diol (A/anediol) in some rodent tissues including brain. To determine whether CYP7B is responsible for these and other activities we disrupted the mouse Cyp7b gene by targeted insertion of an IRES-lacZ reporter cassette, placing reporter enzyme activity (-galactosidase) under Cyp7b promoter control. In heterozygous mouse brain, chromogenic detection of reporter activity was strikingly restricted to the dentate gyrus. Staining did not exactly reproduce the in situ hybridization expression pattern; post-transcriptional control is inferred. Lower level staining was detected in cerebellum, liver, and kidney, and which largely paralleled mRNA distribution. Liver and kidney expression was sexually dimorphic. Mice homozygous for the insertion are viable and superficially normal, but ex vivo metabolism of DHEA to 7-hydroxy-DHEA was abolished in brain, spleen, thymus, heart, lung, prostate, uterus, and mammary gland; lower abundance metabolites were also eliminated. 7-Hydroxylation of 25-hydroxycholesterol and related substrates was also abolished, as was presumed 6-hydroxylation of A/anediol. These different enzyme activities therefore derive from the Cyp7b gene. CYP7B is thus a major extrahepatic steroid and oxysterol hydroxylase and provides the predominant route for local metabolism of DHEA and related molecules in brain and other tissues.

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