Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2,3-Iminosqualene (ISq) is a powerful inhibitor of squalene oxide:lanosterol cyclase (EC 5.4.99.7). When added to lipid-depleted culture media (LDM) of rat hepatoma (H-4-II-E-C3) or Chinese hamster ovary (CHO) cells at a concentration of 10 micrograms ml-1, it causes the cells to float off the substratum in a few days. Lipoproteins in the culture medium completely counteract this effect. Cells in lipoprotein-containing media (FGM) grow normally in the presence of ISq. Irrespective of the culture medium, ISq at 10 micrograms ml-1 causes an almost complete and apparently irreversible inactivation of the squalene oxide cyclase in CHO and H4 cells and the accumulation in the cells of squalene, of squalene 2,3-oxide (mostly), and of squalene 2,3-22,23-dioxide when [14C]acetate or [14C]mevalonate is fed to the cells. Chronic treatment of H4 cells with ISq failed to elicit induction of the cyclase, but increased the conversion of mevalonate into squalene and squalene dioxide, and depressed the conversion of squalene oxide to the dioxide. Cells loaded with squalene and the squalene oxides from mevalonate in the presence of ISq get rid of these substances by rapidly secreting them into the media and by some unidentified metabolic processes.
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PMID:Effects of 2,3-iminosqualene on cultured cells. 289 34

The inhibition of 2,3-oxidosqualene-lanosterol cyclase (EC 5.4.99.7) (OSC) by new azasqualene derivatives, mimicking the proC-8 and proC-20 carbocationic high-energy intermediates of the cyclization of 2,3-oxidosqualene to lanosterol, was studied using pig liver microsomes, partially purified preparations of OSC, and yeast microsomes. The azasqualene derivatives tested were: 6E- and 6Z-10aza-10,11-dihydrosqualene-2,3-epoxide 17 and 18, 19-aza-18,19,22,23-tetrahydrosqualene-2,3-epoxide 19 and its corresponding N-oxide 20, and 19-aza-18,19,22,23-tetrahydrosqualene 21. The compounds 17 and 19 (i.e. the derivatives bearing the 2,3-epoxide ring and the same geometrical configuration as the OSC substrate) were effective inhibitors, as shown by the Ki obtained using partially purified OSC: 2.67 microM and 2.14 microM, respectively. Compound 18, having an incorrect configuration and the 19-aza derivative 21, lacking the 2,3-epoxide ring, were poor inhibitors, with IC50 of 44 microM and 70 microM, respectively. Compound 21 was a competitive inhibitor of OSC, whereas 17 and 19 were noncompetitive inhibitors, and showed a biphasic time-dependent inactivation of OSC, their apparent binding constants being 250 microM and 213 microM, respectively. The inhibition of sterol biosynthesis was studied using human hepatoma HepG2 cells. The incorporation of [14C] acetate in the C27 sterols was reduced by 50% by 0.55 microM 17, 0.22 microM 19, and 0.45 microM 21, whereas 2 microM 18 did not affect sterol biosynthesis. In the presence of 17, 19 and 21, only the intermediate metabolites 2,3-oxidosqualene and 2,3,22,23-dioxidosqualene accumulated, demonstrating a very specific inhibition of OSC.
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PMID:Inhibition of 2,3-oxidosqualene cyclase and sterol biosynthesis by 10- and 19-azasqualene derivatives. 757 39

N-[(1,5,9)-trimethyldecyl]-4 alpha,10-dimethyl-8-aza-trans-decal-3 beta-ol (8-azadecalin 1), a high-energy intermediate analogue for the 2,3-oxidosqualene-lanosterol cyclase, was found to be a powerful (IC50 approximately 0.1 microM) inhibitor of cholesterol biosynthesis in human hepatoma HepG2 cells. In analogy with other mammalian cells grown in the presence of cyclase inhibitors, the decrease in C27-sterol formation was accompanied by an accumulation of 2,3-oxidosqualene, 2,3:22, 23-dioxidosqualene, and by the formation of a compound characterized as 24,25-epoxycholesterol, a repressor of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase activity. In order to assess the cyclase as a potential pharmacological target for the design of hypocholesterolemic drugs, it is important to test whether inhibitors of this enzyme are able to act synergistically on the biosynthesis of cholesterol, i.e. by decreasing the amount of lanosterol formed and by repressing the regulatory HMG-CoA reductase via the formation of regulatory oxysterols. The accumulation of 24,25-epoxycholesterol in relationship to the decrease of C27-sterol biosynthesis and of HMG-CoA reductase activity showed only a partial correlation: e.g. at [1] = 100 x IC50 only a 50% reduction in enzyme activity could be attained. In contrast, when HepG2 cells were treated with 2,3:22,23-dioxidosqualene or 24,25-epoxycholesterol, excellent correlations were found between the inhibition of C27-sterol biosynthesis and the repression of HMG-CoA reductase activity, which was almost complete at the highest concentrations of these epoxides (10(-5) M). Altogether, our results suggest that treatment of HepG2 cells with a cyclase inhibitor such as 8-azadecalin (1) does not lead to an intracellular accumulation of repressor molecules high enough to fully trigger a regulatory pathway resulting in a complete down-regulation of HMG-CoA reductase. At intermediary concentrations of cyclase inhibitors (IC50), however, a synergistic mode of action of these inhibitors seems plausible.
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PMID:Effects of a 2,3-oxidosqualene-lanosterol cyclase inhibitor 2,3:22,23-dioxidosqualene and 24,25-epoxycholesterol on the regulation of cholesterol biosynthesis in human hepatoma cell line HepG2. 804 30