Polypeptide Activators of Cholesterol Side-Chain Cleavage

Pedersen, Robert C.

doi:10.1080/07435808409036515

Cited by 30 publications

(2 citation statements)

References 81 publications

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“…It is generally believed that ACTH (and hence cAMP) increases steroid synthesis as the result of stimulating the transport of cholesterol to the inner mitochondrial membrane (14,15). In the present studies, (Bu) 2 cAMP stimulated transport of cholesterol in cells with high, normal, and low plasma membrane C/P.…”

Section: Discussionsupporting

confidence: 61%

The Influence of Exogenous Free Cholesterol on Steroid Synthesis in Cultured Adrenal Cells*

1989

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Previous studies showed that Y-1 cells in which the concentration of cholesterol in plasma membranes (expressed relative to phospholipid as a molar ratio, C/P) was raised by incubation with cholesterol produced more 20 alpha-dihydroprogesterone than cells with normal or low plasma membrane C/P values. This difference was not associated with any difference in the production of cAMP. The cells respond to (Bu)2cAMP in the order high greater than normal greater than low C/P. High C/P is associated with higher levels of cholesterol in the cytosol and higher concentrations of this steroid in the inner mitochondrial membrane. The rate of transport of cholesterol to the inner membrane differed in the three groups of cells: high greater than normal greater than low C/P. Production of pregnenolone by mitoplasts was no different in the three groups, and the same applies to the production of pregnenolone by mitochondria from cells incubated with and those incubated without (Bu)2cAMP. 25-Hydroxycholesterol increased the production of 20 alpha-dihydroprogesterone by cells showing normal or low C/P values, but not those with high values. It is concluded that the transport of cholesterol to the inner mitochondrial membrane is regulated by at least two processes, namely the supply of substrate (cholesterol), which can saturate this transport mechanism, and some mechanism(s) that is stimulated by cAMP and is capable of stimulating transport above maximal levels produced by high concentrations of cholesterol alone. The second mechanism requires the synthesis of a new protein(s).

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Section: Discussionsupporting

confidence: 61%

The Influence of Exogenous Free Cholesterol on Steroid Synthesis in Cultured Adrenal Cells*

1989

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“…Presumably, it is during this membrane fusion that cholesterol is transferred to the inner membrane (Stocco, 1997). Regardless of the mechanism(s), once cholesterol is mobilized to the inner mitochondrial membrane and positioned next to the cholesterol C 27 -side chain cleavage enzyme, an LH-dependent protein termed sterol-activating protein is thought to facilitate the binding of cholesterol to the P 450 C 27 -side chain cleavage enzyme (Pederson, 1984).…”

Section: A Endocrine Regulation Of Lc Functionmentioning

confidence: 99%

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Cook

Klinefelter

Hardisty

et al. 1999

Critical Reviews in Toxicology

175

122

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Leydig cells (LCs) are the cells of the testis that have as their primary function the production of testosterone. LCs are a common target of compounds tested in rodent carcinogenicity bioassays. The number of reviews on Leydig cell tumors (LCTs) has increased in recent years because of its common occurrence in rodent bioassays and the importance in assessing the relevance of this tumor type to humans. To date, there have been no comprehensive reviews to identify all the compounds that have been shown to induce LCTs in rodents or has any review systematically evaluated the epidemiology data to determine whether humans were at increased risk for developing LCTs from exposure to these agents. This review attempts to fill these deficiencies in the literature by comparing the cytology and ontogeny of the LC, as well as the endocrine and paracrine regulation of both normal and tumorigenic LCs. In addition, the pathology of LCTs in rodents and humans is compared, compounds that induce LC hyperplasia or tumors are enumerated, and the human relevance of chemical-induced LCTs is discussed. There are plausible mechanisms for the chemical induction of LCTs, as typified by agonists of estrogen, gonadotropin releasing hormone (GnRH), and dopamine receptors, androgen receptor antagonists, and inhibitors of 5alpha-reductase, testosterone biosynthesis, and aromatase. Most of these ultimately involve elevation in serum luteinizing hormone (LH) and/or LC responsiveness to LH as proximate mediators. It is expected that further work will uncover additional mechanisms by which LCTs may arise, especially the role of growth factors in modulating LC tumorigenesis. Regarding human relevance, the pathways for regulation of the hypothalamo-pituitary-testis (HPT) axis of rats and humans are similar, such that compounds that either decrease testosterone or estradiol levels or their recognition will increase LH levels. Hence, compounds that induce LCTs in rats by disruption of the HPT axis pose a risk to human health, except for possibly two classes of compounds (GnRH and dopamine agonists). Because GnRH and prolactin receptors are either not expressed or are expressed at very low levels in the testes in humans, the induction of LCTs in rats by GnRH and dopamine agonists would appear not to be relevant to humans; however, the potential relevance to humans of the remaining five pathways of LCT induction cannot be ruled out. Therefore, the central issue becomes what is the relative sensitivity between rat and human LCs in their response to increased LH levels; specifically, is the proliferative stimulus initiated by increased levels of LH attenuated, similar, or enhanced in human vs. rat LCs? There are several lines of evidence that suggest that human LCs are quantitatively less sensitive than rats in their proliferative response to LH, and hence in their sensitivity to chemically induced LCTs. This evidence includes the following: (1) the human incidence of LCTs is much lower than in rodents even when corrected for detection bias; (2) several ...

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Characterization of the Protein Responsible for the Acute Regulation of Steroidogenesis in Mouse Leydig Tumor Cells

Stocco¹,

Clark²,

Lin³

et al. 1996

Cellular and Molecular Regulation of Testicular Cells

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Polypeptide Activators of Cholesterol Side-Chain Cleavage

Cited by 30 publications

References 81 publications

The Influence of Exogenous Free Cholesterol on Steroid Synthesis in Cultured Adrenal Cells*

The Influence of Exogenous Free Cholesterol on Steroid Synthesis in Cultured Adrenal Cells*

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Characterization of the Protein Responsible for the Acute Regulation of Steroidogenesis in Mouse Leydig Tumor Cells

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