A novel inhibitor of steroid biosynthesis

Nelson, James A.; Czarny, Michael R.; Spencer, Thomas A.; Limanek, James S.; McCrae, Keith R.; Chang, Ta Yuan

doi:10.1021/ja00483a050

Cited by 34 publications

(7 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A key discovery in this area was the demonstration that incubation of the 10,000-g supernatant fraction of rat liver homogenate with [2-14 C]mevalonate in the presence of 4,4,10␤-trimethyl-trans-decalin-3␤,7␤-diol inhibited Chol formation and led to the accumulation of 2,3-epoxysqualene and 2,3:22,23-diepoxysqualene (699) (as judged by TLC). Similar findings were also made upon incubation of CHO cells with labeled acetate in the presence of the decalin derivative (699). Subsequent studies (760) with the same compound inhibited the incorporation of Lesser amounts of 14 C were observed to be associated with "epoxycholesterol" and "desmosterol."…”

Section: E Formation Of 2425-epoxysterolssupporting

confidence: 61%

Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Schroepfer

2000

Physiological Reviews

873

687

View full text Add to dashboard Cite

Oxygenated derivatives of cholesterol (oxysterols) present a remarkably diverse profile of biological activities, including effects on sphingolipid metabolism, platelet aggregation, apoptosis, and protein prenylation. The most notable oxysterol activities center around the regulation of cholesterol homeostasis, which appears to be controlled in part by a complex series of interactions of oxysterol ligands with various receptors, such as the oxysterol binding protein, the cellular nucleic acid binding protein, the sterol regulatory element binding protein, the LXR nuclear orphan receptors, and the low-density lipoprotein receptor. Identification of the endogenous oxysterol ligands and elucidation of their enzymatic origins are topics of active investigation. Except for 24, 25-epoxysterols, most oxysterols arise from cholesterol by autoxidation or by specific microsomal or mitochondrial oxidations, usually involving cytochrome P-450 species. Oxysterols are variously metabolized to esters, bile acids, steroid hormones, cholesterol, or other sterols through pathways that may differ according to the type of cell and mode of experimentation (in vitro, in vivo, cell culture). Reliable measurements of oxysterol levels and activities are hampered by low physiological concentrations (approximately 0.01-0.1 microM plasma) relative to cholesterol (approximately 5,000 microM) and by the susceptibility of cholesterol to autoxidation, which produces artifactual oxysterols that may also have potent activities. Reports describing the occurrence and levels of oxysterols in plasma, low-density lipoproteins, various tissues, and food products include many unrealistic data resulting from inattention to autoxidation and to limitations of the analytical methodology. Because of the widespread lack of appreciation for the technical difficulties involved in oxysterol research, a rigorous evaluation of the chromatographic and spectroscopic methods used in the isolation, characterization, and quantitation of oxysterols has been included. This review comprises a detailed and critical assessment of current knowledge regarding the formation, occurrence, metabolism, regulatory properties, and other activities of oxysterols in mammalian systems.

show abstract

Section: E Formation Of 2425-epoxysterolssupporting

confidence: 61%

Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Schroepfer

2000

Physiological Reviews

873

687

View full text Add to dashboard Cite

show abstract

“…Importantly when an aza group was introduced at position 2 in 4,4, 10β-trimethyl- trans -decal-3β-ol (TMD), i . e ., a decalin structure which was previously found to be a cyclase inhibitor, much less inhibition was observed . The same was true for the first generation of isoquinolines …”

Section: Introductionsupporting

confidence: 57%

Structural and Stereoelectronic Requirements for the Inhibition of Mammalian 2,3-Oxidosqualene Cyclase by Substituted Isoquinoline Derivatives

et al. 1996

View full text Add to dashboard Cite

2,3-Oxidosqualene lanosterol-cyclase (OSC; EC 5.4.99.7) is an attractive target for the design of compounds that block hepatic cholesterol biosynthesis. (4a alpha, 5 alpha, 6 beta, 8a beta)-Decahydro-5,8a-dimethyl-2-(1,5,9-trimethyldecyl)-6- isoquinolinol (1) and simplified analogs have been devised to inhibit this enzyme by mimicking the postulated pro-C-8 high-energy intermediary carbocation occurring during the cyclization-rearrangement pathway. In order to gain an understanding into the mechanism by which these types of molecules inhibit OSC, we have synthesized a series of substituted isoquinoline derivatives 3 and investigated the structural and stereoelectronic requirements, and their stringency, that make 3 potential high-energy intermediate analogs of OSC. Determination of the IC50 values of the different compounds with rat liver microsomal cyclase, allowed the study of the relative importance of (i) the nature and the stereochemistry of the nitrogen side chain, (ii) the presence of methyl groups at C-5 and C-8a (ring junction), (iii) the presence and stereochemistry of the C-6 hydroxyl group, (iv) the nature of the ring junction, and (v) the absolute configuration of the bicyclic system. The resulting structure-activity relationships seem to validate the mechanism of action of these inhibitors as analogs of a pro-C-8 high-energy intermediate and delineate the minimal requirements for the design of efficient isoquinoline-based, or simplified, OSC inhibitors.

show abstract

“…We also employ compactin as a specific inhibitor of HMG-CoA reductase (Endo et al, 1976) and trans-4,4,10/3-trimethyldecal-30-ol (TMD) as a specific inhibitor of squalene-oxide cyclase (Nelson et al, 1978;Chang et al, 1979) to study the effect of blocking endogenous sterol synthesis on cycloheximide activation of ACAT. Finally, the cycloheximide effect is examined in a CHO cell mutant (mutant 1) requiring exogenous cholesterol for growth (Limanek et al, 1978;Chin & Chang, 1981.…”

mentioning

confidence: 99%

Cycloheximide sensitivity in regulation of acyl coenzyme A:cholesterol acyltransferase activity in Chinese hamster ovary cells. 2. Effect of sterol endogenously synthesized

Chang¹,

Chang²

1986

Biochemistry

View full text Add to dashboard Cite

We reported in another paper [Chang, C. C. Y., Doolittle, G. M., & Chang, T. Y. (1986) Biochemistry (preceding paper in this issue)] that in Chinese hamster ovary (CHO) cells activation of acyl coenzyme A:cholesterol acyltransferase (ACAT) activity by treating cells with cycloheximide was abolished by providing exogenous sterol in the medium. We now report that providing 20 mM DL-mevalonate to cells grown in sterol-free medium increases the ACAT activity by approximately 6-fold and diminishes the cycloheximide activation effect. The mevalonate supplement has no significant effect on the rate of triglyceride or polar lipid synthesis, [3H]cholesterol efflux, or bulk protein degradation in cells. The activation of ACAT by mevalonate is prevented by adding a specific squalene oxide cyclase inhibitor to cells, indicating the requirement for endogenous sterol synthesis to mediate the mevalonate effect. In sterol-free medium, if sterol synthesis is blocked by specific enzyme inhibitors or through mutation, the ACAT activation by cycloheximide is again abolished. These results support the hypothesis that there may exist a short-lived factor(s) serving directly or indirectly as an endogenous ACAT inhibitor(s), the inhibitory action of this (these) factor(s) is (are) abolished, and its (their) turnover rate(s) is (are) increased by either exogenous sterol or by sterol endogenously synthesized. Conversely, removing exogenous sterol coupled with blocking endogenous sterol synthesis decreases the turnover rate(s) of the inhibitor(s), rendering its (their) action insensitive to intracellular degradation over the time period studied.

show abstract

A novel inhibitor of steroid biosynthesis

Cited by 34 publications

References 1 publication

Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Structural and Stereoelectronic Requirements for the Inhibition of Mammalian 2,3-Oxidosqualene Cyclase by Substituted Isoquinoline Derivatives

Cycloheximide sensitivity in regulation of acyl coenzyme A:cholesterol acyltransferase activity in Chinese hamster ovary cells. 2. Effect of sterol endogenously synthesized

Contact Info

Product

Resources

About