Novel oxysterols observed in tissues and fluids of AY9944-treated rats: a model for Smith-Lemli-Opitz syndrome

Xu, Libin; Liu, Wei; Sheflin, Lowell G.; Fliesler, Steven J.; Porter, Ned A.

doi:10.1194/jlr.m018366

Cited by 63 publications

(120 citation statements)

References 75 publications

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“…1) follow from the mechanism we proposed for trans-1-phenyl-1-butene (38). Beyond this work and that of Mansuy et al (37), we are unaware of more precedents or previous searches for substrates that undergo such reactions. Presumably, more P450 reactions exist that involve rather exclusive conversion of an olefin to a carbonyl, although these cannot be predicted.…”

Section: -Ketocholesterol Formation By Cytochrome P450 7a1mentioning

confidence: 75%

“…SLOS). The product, 7-ketocholesterol, is associated with several disease states and has been shown to accumulate in an animal model for SLOS (37). We propose that, in the absence of other enzymes that form 7-ketocholesterol, the enzyme reaction demonstrated here may be a source of 7-keto bile acids.…”

Section: -Ketocholesterol Formation By Cytochrome P450 7a1mentioning

confidence: 90%

“…Recently, 7-ketocholesterol was found to accumulate in AY9944 (an inhibitor of DHCR7)-treated rats (37), where 7-dehydrocholesterol is the dominant sterol precursor. Although it seems unusual to observe higher levels of 7-ketocholesterol with decreased levels of cholesterol, our results here on 7-dehydrocholesterol being an alternative precursor to 7-ketocholesterol provide a reasonable explanation for this observation.…”

Section: -Ketocholesterol Formation By Cytochrome P450 7a1mentioning

confidence: 99%

“…7-Ketocholesterol was not among the many identified oxysterols in the free radical oxidation of 7-dehydrocholesterol (12). However, in a recent study, 7-ketocholesterol was one of the major oxysterols observed in a rat model for SLOS, in which 7-dehydrocholesterol is the dominant sterol (37).…”

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confidence: 99%

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Conversion of 7-Dehydrocholesterol to 7-Ketocholesterol Is Catalyzed by Human Cytochrome P450 7A1 and Occurs by Direct Oxidation without an Epoxide Intermediate

Shinkyo

Tallman

et al. 2011

Journal of Biological Chemistry

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Section: -Ketocholesterol Formation By Cytochrome P450 7a1mentioning

confidence: 75%

Section: -Ketocholesterol Formation By Cytochrome P450 7a1mentioning

confidence: 90%

Section: -Ketocholesterol Formation By Cytochrome P450 7a1mentioning

confidence: 99%

mentioning

confidence: 99%

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Conversion of 7-Dehydrocholesterol to 7-Ketocholesterol Is Catalyzed by Human Cytochrome P450 7A1 and Occurs by Direct Oxidation without an Epoxide Intermediate

Shinkyo

Tallman

et al. 2011

Journal of Biological Chemistry

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“…We are aware that 7DHC enrichment of the T cell membrane using MβCD and the consequent altered ratio of 7DHC/CHOL only partly mimics the SLOS plasma membrane. For example, other species of CHOL precursors and 7DHC-derived oxysterols were not present in the T cells treated with MβCD complexed to CHOL or 7DHC whereas these compounds are identified in SLOS cells [7,8,66,67]. Nevertheless, 7DHC is the prominent sterol in the SLOS membrane and the biophysical parameters of Kv1.3 gating were similarly affected in SLOS and in T cells treated with MβCD/7DHC complex.…”

Section: Discussionmentioning

confidence: 99%

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

Balajthy

Somodi

Pethő

et al. 2016

Pflugers Arch - Eur J Physiol

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In vitro manipulation of membrane sterol level affects the regulation of ion channels and consequently certain cellular functions; however, a comprehensive study that confirms the pathophysiological significance of these results is missing. The malfunction of 7-dehydrocholesterol (7DHC) reductase in Smith-Lemli-Opitz syndrome (SLOS) leads to the elevation of the 7-dehydrocholesterol level in the plasma membrane. T lymphocytes were isolated from SLOS patients to assess the effect of the in vivo altered membrane sterol composition on the operation of the voltage-gated Kv1.3 channel and the ion channel-dependent mitogenic responses. We found that the kinetic and equilibrium parameters of Kv1.3 activation changed in SLOS cells. Identical changes in Kv1.3 operation were observed when control/healthy T cells were loaded with 7DHC. Removal of the putative sterol binding sites on Kv1.3 resulted in a phenotype that was not influenced by the elevation in membrane sterol level. Functional assays exhibited impaired activation and proliferation rate of T cells probably partially due to the modified Kv1.3 operation. We concluded that the altered membrane sterol composition hindered the operation of Kv1.3 as well as the ion channel-controlled T cell functions.

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7‐Dehydrocholesterol Encapsulated Polymeric Nanoparticles As a Radiation‐Responsive Sensitizer for Enhancing Radiation Therapy

Delahunty

Jiang

et al. 2022

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Therapeutics that can be activated by radiation in situ to enhance the efficacy of radiotherapy are highly desirable. Herein, 7‐Dehydrocholesterol (7‐DHC), a biosynthetic precursor of cholesterol, as a radiosensitizer, exploiting its ability to propagate the free radical chain reaction is explored. The studies show that 7‐DHC can react with radiation‐induced reactive oxygen species and in turn promote lipid peroxidation, double‐strand breaks, and mitochondrial damage in cancer cells. For efficient delivery, 7‐DHC is encapsulated into poly(lactic‐co‐glycolic acid) nanoparticles, forming 7‐DHC@PLGA NPs. When tested in CT26 tumor bearing mice, 7‐DHC@PLGA NPs significantly enhanced the efficacy of radiotherapy, causing complete tumor eradication in 30% of the treated animals. After treatment, 7‐DHC is converted to cholesterol, causing no detectable side effects or hypercalcemia. 7‐DHC@PLGA NPs represent a radiation‐responsive sensitizer with great potential in clinical translation.

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Novel oxysterols observed in tissues and fluids of AY9944-treated rats: a model for Smith-Lemli-Opitz syndrome

Cited by 63 publications

References 75 publications

Conversion of 7-Dehydrocholesterol to 7-Ketocholesterol Is Catalyzed by Human Cytochrome P450 7A1 and Occurs by Direct Oxidation without an Epoxide Intermediate

Conversion of 7-Dehydrocholesterol to 7-Ketocholesterol Is Catalyzed by Human Cytochrome P450 7A1 and Occurs by Direct Oxidation without an Epoxide Intermediate

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

7‐Dehydrocholesterol Encapsulated Polymeric Nanoparticles As a Radiation‐Responsive Sensitizer for Enhancing Radiation Therapy

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