The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the conversion of HMG-CoA to mevalonate, a four-electron oxidoreduction that is the rate-limiting step in the synthesis of cholesterol and other isoprenoids[3]. SR-12813 inhibits cholesterol biosynthesis in Hep G2 cells via an enhanced degradation of HMG-CoA reductase. After 7 days plasma cholesterol was decreased by 15% in the 10 mg/kg/day group and by 19% in the 25 mg/kg/day group[4]. SR-12813 inhibited incorporation of tritiated water into cholesterol with an IC50 of 1.2 mM but had no effect on fatty acid synthesis. Furthermore, SR-12813 reduced cellular HMG-CoA reductase activity with an IC50 of 0.85 mM. The inhibition of HMG-CoA reductase activity was rapid with a T1/2 of 10 min. After a 16-h incubation with SR-12813, mRNA levels of HMG-CoA reductase and low density lipoprotein (LDL) receptor were increased. The increased expression of LDL receptor translated into a higher LDL uptake, which can explain the primary hypocholesterolemic effect of SR-12813 in vivo[5]. Treatment of hCMEC/D3 cells for 72 hr with rifampin or SR12813 (two well-established hPXR ligands) or PIs (atazanavir or ritonavir) resulted in an increase in P-gp expression by 1.8-, 6-, and 2-fold, respectively, with no effect observed for MRP1 expression[6]. Preactivation of hPXR by SR12813 in MDA-MB-231 cells led to an increased resistance to Taxol at concentrations of 20 and 50 nM[7].
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