Aminoglutethimide, a Steroidogenesis Inhibitor, Abolishes Hormonal Induction of Ornithine Decarboxylase in Steroidogenic Tissues: Evidence for Its Role as cAMP-Dependent Protein Kinase Inhibitor

Bastida, C.M.; Tejada, Francisco; Cremades, Adolfo Díaz-Bautista; Peñafiel, Rafael

doi:10.1006/bbrc.2001.4332

Cited by 5 publications

(2 citation statements)

References 33 publications

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“…In order to verify that corticosterone was the likely mediator of the effect, a corticosterone synthesis inhibitor, aminoglutethimide was utilized. Aminoglutethimide modulates corticosterone synthesis by blocking P450scc (cytochrome P450 side chain cleavage), involved in corticosterone biosynthesis from cholesterol (Bastida et al, 2001). As was seen in the ADX studies, the aminoglutethimide also blocked thymic atrophy by SMD.…”

Section: Discussionmentioning

confidence: 59%

Sodium Methyldithiocarbamate Causes Thymic Atrophy by an Indirect Mechanism of Corticosterone Up-Regulation

Myers

Fan

Zheng

et al. 2005

Journal of Immunotoxicology

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Sodium methyldithiocarbamate (SMD) is an agricultural fumigant-type pesticide commonly used as a pre-plant biocide. SMD is currently listed by the US Environmental Protection Agency (EPA) as the third most commonly used conventional pesticide. Previously, SMD has been shown to be immunotoxic in mice. Initial immunotoxicological studies indicated that thymocytes are major targets of SMD or its breakdown products in mice. The purpose of the present study was to determine if this effect was mediated by an SMD-induced stress response. The decrease in thymus weight correlated to a decrease in all thymocyte subpopulations. However, as seen in earlier studies, the double positive (CD4 + CD8 + ) thymocyte subpopulation was more selectively decreased than the other subpopulations. The double negative (CD4 − CD8 − ) and single positive (CD4 + CD8 − or CD4 − CD8 + ) thymocyte subpopulations decreased in absolute numbers while increasing in percentage of the remaining cells in the thymus after SMD intoxication. In the current study, SMD caused an increase in serum corticosterone, a stress-related hormone. Blocking corticosterone either by 1) adrenalectomy or by 2) chemically blocking synthesis of nascent corticosterone in adrenal-competent animals abrogated the thymocyte atrophy caused by SMD. However, an additional stressor (restraint) did not act additively or synergistically to increase atrophy. Therefore, it is likely that SMD causes thymic atrophy by increasing serum corticosterone.

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Section: Discussionmentioning

confidence: 59%

Sodium Methyldithiocarbamate Causes Thymic Atrophy by an Indirect Mechanism of Corticosterone Up-Regulation

Myers

Fan

Zheng

et al. 2005

Journal of Immunotoxicology

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“… Bastida et al . (2001) have reported that aminoglutethimide may act as an inhibitor of protein kinase A.…”

Section: Resultsmentioning

confidence: 99%

Aminoglutethimide prevents excitotoxic and ischemic injuries in cortical neurons

Shirakawa

Katsuki

Kume

et al. 2006

British J Pharmacology

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Aminoglutethimide is a clinically available drug that suppresses steroid biosynthesis by inhibiting enzymes such as cytochrome P450scc and aromatase. Because several members of neurosteroids regulate glutamate receptors, we investigated the effect of aminoglutethimide on cell death induced by overactivation of glutamate receptors in CNS neurons. Long-term pretreatment of organotypic cerebrocortical slice cultures with aminoglutethimide (100-1000 microM) for 6 days or over resulted in concentration-dependent suppression of neuronal cell death induced by NMDA. Aminoglutethimide (1000 microM) also inhibited neurotoxicity of AMPA and kainate, but not of ionomycin or staurosporine. The protective effect of aminoglutethimide against NMDA cytotoxicity was not mimicked by other steroid synthesis inhibitors including trilostane and exemestane, and was not reversed by concurrent application of steroids such as pregnenolone, estrone, 17beta-estradiol and estriol. In dissociated rat cerebrocortical cell cultures, long-term treatment with aminoglutethimide (10-1000 microM) attenuated NMDA receptor-mediated glutamate cytotoxicity but produced no significant effect on glutamate-induced increases in intracellular Ca2+. Brief as well as long-term pretreatment with aminoglutethimide (30-1000 microM) prevented NMDA receptor-dependent ischemic neuronal injury in organotypic cerebrocortical slice cultures, which was associated with suppression of glutamate release during the ischemic insult. These results indicate that aminoglutethimide, irrelevant to its actions on neurosteroid synthesis, protects CNS neurons from excitotoxic and ischemic injuries. Development of aminoglutethimide analogs possessing neuroprotective properties may be of therapeutic value.

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The H295R system for evaluation of endocrine-disrupting effects

Gracia

Hilscherová

Jones

et al. 2006

Ecotoxicology and Environmental Safety

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Aminoglutethimide, a Steroidogenesis Inhibitor, Abolishes Hormonal Induction of Ornithine Decarboxylase in Steroidogenic Tissues: Evidence for Its Role as cAMP-Dependent Protein Kinase Inhibitor

Cited by 5 publications

References 33 publications

Sodium Methyldithiocarbamate Causes Thymic Atrophy by an Indirect Mechanism of Corticosterone Up-Regulation

Sodium Methyldithiocarbamate Causes Thymic Atrophy by an Indirect Mechanism of Corticosterone Up-Regulation

Aminoglutethimide prevents excitotoxic and ischemic injuries in cortical neurons

The H295R system for evaluation of endocrine-disrupting effects

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