Central Administration of a Cytochrome P450-7B Product 7α-Hydroxypregnenolone Improves Spatial Memory Retention in Cognitively Impaired Aged Rats

Yau, Joyce L.W.; Noble, June; Graham, M. K.

doi:10.1523/jneurosci.3189-06.2006

Cited by 30 publications

(16 citation statements)

References 50 publications

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“…Indeed, some of the beneficial cognitive (613,660,791,794) and atheroprotective (282, 493) effects of 11␤-HSD1 deficiency or inhibition may, in part, reflect decreased metabolism of nonglucocorticoid substrates (792).…”

Section: ␤-Hsd1: Nonglucocorticoid Substratesmentioning

confidence: 99%

“…Additionally, 7-keto-and 7␤-hydroxy derivatives of the neurosteroids dehydroepiandrosterone (DHEA) and pregnenolone can be metabolized by 11␤-HSD1 (515). Intriguingly, DHEA and pregnenolone modified in the 7-position potentiate neurosteroid activity, producing cognitive enhancement with ageing (792). Any involvement of 11␤-HSD1 in these reactions is unaddressed.…”

Section: Oxysterolsmentioning

confidence: 99%

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11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

734

601

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Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

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Section: ␤-Hsd1: Nonglucocorticoid Substratesmentioning

confidence: 99%

Section: Oxysterolsmentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

734

601

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“…CYP7B1 is a human enzyme; its murine homolog is expressed primarily in the brain and at low levels in the liver 30 . Its 7α-hydroxylated steroid products are poorly understood, but improve memory in aged, memory-impaired mice 28,31 . While 7 is not present in the human body, 3 is an intermediate formed by CYP17A1 in the adrenal cortex and gonads 32 .…”

Section: Cc-by-nc-ndmentioning

confidence: 99%

Mammalian Cells Engineered to Produce Novel Steroids

Spady

Wyche

Rollins

et al. 2018

Preprint

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Steroids can be difficult to modify via traditional organic synthesis methods, but many enzymes regio-and stereo-selectively process a wide variety of steroid substrates. We tested whether steroid-modifying enzymes could make novel steroids from non-native substrates. Numerous genes encoding steroid-modifying enzymes, including some bacterial enzymes, were expressed in mammalian cells by transient transfection and found to be active. We made three unusual steroids by expression in HEK293 cells of the 7α-hydroxylase CYP7B1, which was selected because of high native product yield. These cells made 7α,17α-dihydroxypregnenolone and 7β,17α-dihydroxypregnenolone from 17α-hydroxypregnenolone, and produced 11α,16α-dihydroxyprogesterone from 16α-hydroxyprogesterone. The latter two products resulted from previously unobserved CYP7B1 hydroxylation sites. A Rosetta docking model of CYP7B1 suggested that these substrates' D-ring hydroxylations may prevent them from binding in the same way as the native substrate, bringing different carbons near the active ferryl oxygen. This new approach could use other enzymes and substrates to produce many novel steroids for drug candidate testing.

show abstract

“…CYP7B1 is a human enzyme; its murine homologue is expressed primarily in the brain and at low levels in the liver . Its 7α‐hydroxylated steroid products are poorly understood, but improve memory in aged, memory‐impaired mice . Although 7 has not been observed in the human body, 3 is an intermediate formed by CYP17A1 in the adrenal cortex and gonads .…”

Section: Figurementioning

confidence: 99%

Mammalian Cells Engineered To Produce New Steroids

et al. 2018

View full text Add to dashboard Cite

Steroids can be difficult to modify via traditional organic synthesis methods, but many enzymes regio- and stereo-selectively process a wide variety of steroid substrates. We tested whether steroid-modifying enzymes could make novel steroids from non-native substrates. Numerous genes encoding steroid-modifying enzymes, including some bacterial enzymes, were expressed in mammalian cells by transient transfection and found to be active. We made three unusual steroids by stable expression in HEK293 cells of the 7α-hydroxylase CYP7B1, which was selected because of high native product yield. These cells made 7α,17α-dihydroxypregnenolone and 7β,17α-dihydroxypregnenolone from 17α-hydroxypregnenolone, and produced 11α, 16α-dihydroxyprogesterone from 16α-hydroxyprogesterone. The latter two products resulted from previously unobserved CYP7B1 hydroxylation sites. A Rosetta docking model of CYP7B1 suggested that these substrates’ D-ring hydroxylations may prevent them from binding in the same way as the native substrate, bringing different carbons near the active ferryl oxygen. This new approach could use other enzymes and substrates to produce many novel steroids for drug candidate testing.

show abstract

Central Administration of a Cytochrome P450-7B Product 7α-Hydroxypregnenolone Improves Spatial Memory Retention in Cognitively Impaired Aged Rats

Cited by 30 publications

References 50 publications

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Mammalian Cells Engineered to Produce Novel Steroids

Mammalian Cells Engineered To Produce New Steroids

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