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Kamlesh P. Vyas - One of the best experts on this subject based on the ideXlab platform.
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biotransformation of Lovastatin iv identification of cytochrome p450 3a proteins as the major enzymes responsible for the oxidative metabolism of Lovastatin in rat and human liver microsomes
Archives of Biochemistry and Biophysics, 1991Co-Authors: Regina W. Wang, P H Kari, Paul E Thomas, Peter F Guengerich, Anthony Y.h. Lu, Kamlesh P. VyasAbstract:Previous studies from our laboratories have shown that the metabolism of the cholesterol-lowering drug Lovastatin by rat and human liver microsomes occurs primarily at the 6′-position, giving 6′β-hydroxy- and 6′-exomethylene-Lovastatin and that these oxidations are catalyzed by cytochrome P450-dependent monooxygenases. In the present study, the specific cytochrome P450 form involved in Lovastatin oxidation was identified through immunoinhibition studies. Among several antibodies prepared against various cytochrome P450s, only anti-rat P450 3A IgG inhibited Lovastatin metabolism in liver microsomes from untreated, phenobarbital treated, and pregnenolone-16α-carbonitrile-treated rats. Lovastatin metabolism at the 6′-position was markedly inhibited (6′β-hydroxy, greater than 95%; 6′-exomethylene, 70–80%) by this antibody whereas the effect of anti-rat P450 3A on the 3″-hydroxylation was variable depending on the source of the microsomes. With human liver microsomes, both anti-rat P450 3A and anti-human P450 3A inhibited Lovastatin metabolism. Correlation between Lovastatin oxidation and the P450 3A content in human liver microsomes (measured by immunoblot analysis) was excellent (r2 = 0.97). In addition, preincubation of human liver microsomes with troleandomycin and NADPH inhibited metabolism by 60%. These results clearly indicate that cytochrome P450 3A enzymes are primarily responsible for the metabolism of Lovastatin in rat and human liver microsomes.
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biotransformation of Lovastatin iv identification of cytochrome p450 3a proteins as the major enzymes responsible for the oxidative metabolism of Lovastatin in rat and human liver microsomes
Archives of Biochemistry and Biophysics, 1991Co-Authors: Regina W. Wang, P H Kari, Paul E Thomas, Peter F Guengerich, Kamlesh P. VyasAbstract:Previous studies from our laboratories have shown that the metabolism of the cholesterol-lowering drug Lovastatin by rat and human liver microsomes occurs primarily at the 6'-position, giving 6' beta-hydroxy- and 6'-exomethylene-Lovastatin and that these oxidations are catalyzed by cytochrome P450-dependent monooxygenases. In the present study, the specific cytochrome P450 form involved in Lovastatin oxidation was identified through immunoinhibition studies. Among several antibodies prepared against various cytochrome P450s, only anti-rat P450 3A IgG inhibited Lovastatin metabolism in liver microsomes from untreated, phenobarbital-treated, and pregnenolone-16 alpha-carbonitrile-treated rats. Lovastatin metabolism at the 6'-position was markedly inhibited (6' beta-hydroxy, greater than 95%; 6'-exomethylene, 70-80%) by this antibody whereas the effect of anti-rat P450 3A on the 3"-hydroxylation was variable depending on the source of the microsomes. With human liver microsomes, both anti-rat P450 3A and anti-human P450 3A inhibited Lovastatin metabolism. Correlation between Lovastatin oxidation and the P450 3A content in human liver microsomes (measured by immunoblot analysis) was excellent (r2 = 0.97). In addition, preincubation of human liver microsomes with troleandomycin and NADPH inhibited metabolism by 60%. These results clearly indicate that cytochrome P450 3A enzymes are primarily responsible for the metabolism of Lovastatin in rat and human liver microsomes.
Tienchun Chang - One of the best experts on this subject based on the ideXlab platform.
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Lovastatin suppresses invasiveness of anaplastic thyroid cancer cells by inhibiting rho geranylgeranylation and rhoa rock signaling
Endocrine-related Cancer, 2005Co-Authors: Wenbin Zhong, Chihyuan Wang, Y C Liang, Tienchun ChangAbstract:Lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, inhibits the conversion of mevalonate from HMG-CoA. Previously, we have reported that Lovastatin treatment induced the occurrence of apoptosis and differentiation in ARO anaplastic thyroid cancer cells. Here, we demonstrated that Lovastatin inhibited the ARO cell invasiveness and delineated the underlying molecular mechanism. Lovastatin significantly suppressed the EGF-induced cell adhesion, actin filament reorganization and transmigration. Lovastatin also reduced EGF-induced increases in the levels of phosphorylated p125 FAK and paxillin. These inhibitory effects mediated by Lovastatin can be prevented by pretreatment of the cells with mevalonate or geranylgeraniol (GGOH), but not farnesol (FOH). Accordingly, the consuming and depletion of geranylgeranyl pyrophosphate and consequent suppression of the protein geranylgeranylation, which is essential for activation of Rho GTPases, might account for the Lovastatin-induced inhibition of cell motility and invasion. Western blot analysis showed that Lovastatin inhibited membrane translocation of Rho (e.g. RhoA and Rac1) through decreasing post-translational geranylgeranyl modification of Rho. In addition, treatment of the cells with specific inhibitors against Rho (Clostridium botulinum C3 transferase) or ROCK (Y-27632) abolished the GGOH-mediated prevention of, and restored the Lovastatin-induced decrease of cell invasion. Taken together, our results suggested that Lovastatin suppressed EGF-induced ARO cell invasiveness through the reduction of Rho geranylgeranylation, which in turn suppressed the membrane translocation, and subsequent suppression of Rho/ROCK and FAK/paxillin signaling.
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Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis
Endocrinology, 2003Co-Authors: Wenbin Zhong, Chihyuan Wang, Tienchun Chang, Wen Sen LeeAbstract:Lovastatin has been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Inhibition of mevalonate synthesis may result in antiproliferation and cell apoptosis. The aim of the present study was to examine the apoptotic effect of Lovastatin in human ARO cells and delineate its underlying molecular mechanism. Our results showed that Lovastatin dose- and time-dependently induced apoptosis in ARO cells. Pretreatment with cycloheximide dose-dependently suppressed Lovastatin-induced apoptosis, suggesting that de novo protein synthesis is required for Lovastatin effect on the induction of apoptosis in ARO cells. Treatment of the cells with 50 microM Lovastatin induced cytochrome c translocation from mitochondria to cytosol; increases in caspase-2, -3, and -9 activity; and poly (ADP-ribose) polymerase degradation in a time-dependent manner. However, administration of mevalonate or geranylgeraniol, but not farnesol, dose-dependently prevented Lovastatin-induced poly (ADP-ribose) polymerase degradation and the occurrence of apoptosis, but treatment with geranylgeranyl transferase inhibitor, GGTI-298, which blocks the geranylgeranylation, induced an increase in the percentage of the apoptotic cells. These data suggest that geranylgeranylation is required for survival of the Lovastatin-treated ARO cells. To support this notion, we demonstrate that Lovastatin dose-dependently decreased the translocation of RhoA and Rac1, but not Ras, from cytosol to membrane fraction. Moreover, the Lovastatin-induced translocation inhibitions in RhoA and Rac1 were prevented by mevalonate and geranylgeraniol but not farnesol. In conclusion, our data suggest that Lovastatin induced apoptosis in ARO cells by inhibiting protein geranylgeranylation of the Rho family but not farnesylation of the Ras family.
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Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis
Endocrinology, 2003Co-Authors: Wenbin Zhong, Chihyuan Wang, Tienchun ChangAbstract:Lovastatin has been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Inhibition of mevalonate synthesis may result in antiproliferation and cell apoptosis. The aim of the present study was to examine the apoptotic effect of Lovastatin in human ARO cells and delineate its underlying molecular mechanism. Our results showed that Lovastatin dose- and time-dependently induced apoptosis in ARO cells. Pretreatment with cycloheximide dose-dependently suppressed Lovastatin-induced apoptosis, suggesting that de novo protein synthesis is required for Lovastatin effect on the induction of apoptosis in ARO cells. Treatment of the cells with 50 μm Lovastatin induced cytochrome c translocation from mitochondria to cytosol; increases in caspase-2, -3, and -9 activity; and poly (ADP-ribose) polymerase degradation in a time-dependent manner. However, administration of mevalonate or geranylgeraniol, but not farnesol, dose-dependently prevented Lovastatin-induced poly (ADP-ribose) poly...
Chihyuan Wang - One of the best experts on this subject based on the ideXlab platform.
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Lovastatin suppresses invasiveness of anaplastic thyroid cancer cells by inhibiting rho geranylgeranylation and rhoa rock signaling
Endocrine-related Cancer, 2005Co-Authors: Wenbin Zhong, Chihyuan Wang, Y C Liang, Tienchun ChangAbstract:Lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, inhibits the conversion of mevalonate from HMG-CoA. Previously, we have reported that Lovastatin treatment induced the occurrence of apoptosis and differentiation in ARO anaplastic thyroid cancer cells. Here, we demonstrated that Lovastatin inhibited the ARO cell invasiveness and delineated the underlying molecular mechanism. Lovastatin significantly suppressed the EGF-induced cell adhesion, actin filament reorganization and transmigration. Lovastatin also reduced EGF-induced increases in the levels of phosphorylated p125 FAK and paxillin. These inhibitory effects mediated by Lovastatin can be prevented by pretreatment of the cells with mevalonate or geranylgeraniol (GGOH), but not farnesol (FOH). Accordingly, the consuming and depletion of geranylgeranyl pyrophosphate and consequent suppression of the protein geranylgeranylation, which is essential for activation of Rho GTPases, might account for the Lovastatin-induced inhibition of cell motility and invasion. Western blot analysis showed that Lovastatin inhibited membrane translocation of Rho (e.g. RhoA and Rac1) through decreasing post-translational geranylgeranyl modification of Rho. In addition, treatment of the cells with specific inhibitors against Rho (Clostridium botulinum C3 transferase) or ROCK (Y-27632) abolished the GGOH-mediated prevention of, and restored the Lovastatin-induced decrease of cell invasion. Taken together, our results suggested that Lovastatin suppressed EGF-induced ARO cell invasiveness through the reduction of Rho geranylgeranylation, which in turn suppressed the membrane translocation, and subsequent suppression of Rho/ROCK and FAK/paxillin signaling.
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Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis
Endocrinology, 2003Co-Authors: Wenbin Zhong, Chihyuan Wang, Tienchun Chang, Wen Sen LeeAbstract:Lovastatin has been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Inhibition of mevalonate synthesis may result in antiproliferation and cell apoptosis. The aim of the present study was to examine the apoptotic effect of Lovastatin in human ARO cells and delineate its underlying molecular mechanism. Our results showed that Lovastatin dose- and time-dependently induced apoptosis in ARO cells. Pretreatment with cycloheximide dose-dependently suppressed Lovastatin-induced apoptosis, suggesting that de novo protein synthesis is required for Lovastatin effect on the induction of apoptosis in ARO cells. Treatment of the cells with 50 microM Lovastatin induced cytochrome c translocation from mitochondria to cytosol; increases in caspase-2, -3, and -9 activity; and poly (ADP-ribose) polymerase degradation in a time-dependent manner. However, administration of mevalonate or geranylgeraniol, but not farnesol, dose-dependently prevented Lovastatin-induced poly (ADP-ribose) polymerase degradation and the occurrence of apoptosis, but treatment with geranylgeranyl transferase inhibitor, GGTI-298, which blocks the geranylgeranylation, induced an increase in the percentage of the apoptotic cells. These data suggest that geranylgeranylation is required for survival of the Lovastatin-treated ARO cells. To support this notion, we demonstrate that Lovastatin dose-dependently decreased the translocation of RhoA and Rac1, but not Ras, from cytosol to membrane fraction. Moreover, the Lovastatin-induced translocation inhibitions in RhoA and Rac1 were prevented by mevalonate and geranylgeraniol but not farnesol. In conclusion, our data suggest that Lovastatin induced apoptosis in ARO cells by inhibiting protein geranylgeranylation of the Rho family but not farnesylation of the Ras family.
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Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis
Endocrinology, 2003Co-Authors: Wenbin Zhong, Chihyuan Wang, Tienchun ChangAbstract:Lovastatin has been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Inhibition of mevalonate synthesis may result in antiproliferation and cell apoptosis. The aim of the present study was to examine the apoptotic effect of Lovastatin in human ARO cells and delineate its underlying molecular mechanism. Our results showed that Lovastatin dose- and time-dependently induced apoptosis in ARO cells. Pretreatment with cycloheximide dose-dependently suppressed Lovastatin-induced apoptosis, suggesting that de novo protein synthesis is required for Lovastatin effect on the induction of apoptosis in ARO cells. Treatment of the cells with 50 μm Lovastatin induced cytochrome c translocation from mitochondria to cytosol; increases in caspase-2, -3, and -9 activity; and poly (ADP-ribose) polymerase degradation in a time-dependent manner. However, administration of mevalonate or geranylgeraniol, but not farnesol, dose-dependently prevented Lovastatin-induced poly (ADP-ribose) poly...
Wenbin Zhong - One of the best experts on this subject based on the ideXlab platform.
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Lovastatin suppresses invasiveness of anaplastic thyroid cancer cells by inhibiting rho geranylgeranylation and rhoa rock signaling
Endocrine-related Cancer, 2005Co-Authors: Wenbin Zhong, Chihyuan Wang, Y C Liang, Tienchun ChangAbstract:Lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, inhibits the conversion of mevalonate from HMG-CoA. Previously, we have reported that Lovastatin treatment induced the occurrence of apoptosis and differentiation in ARO anaplastic thyroid cancer cells. Here, we demonstrated that Lovastatin inhibited the ARO cell invasiveness and delineated the underlying molecular mechanism. Lovastatin significantly suppressed the EGF-induced cell adhesion, actin filament reorganization and transmigration. Lovastatin also reduced EGF-induced increases in the levels of phosphorylated p125 FAK and paxillin. These inhibitory effects mediated by Lovastatin can be prevented by pretreatment of the cells with mevalonate or geranylgeraniol (GGOH), but not farnesol (FOH). Accordingly, the consuming and depletion of geranylgeranyl pyrophosphate and consequent suppression of the protein geranylgeranylation, which is essential for activation of Rho GTPases, might account for the Lovastatin-induced inhibition of cell motility and invasion. Western blot analysis showed that Lovastatin inhibited membrane translocation of Rho (e.g. RhoA and Rac1) through decreasing post-translational geranylgeranyl modification of Rho. In addition, treatment of the cells with specific inhibitors against Rho (Clostridium botulinum C3 transferase) or ROCK (Y-27632) abolished the GGOH-mediated prevention of, and restored the Lovastatin-induced decrease of cell invasion. Taken together, our results suggested that Lovastatin suppressed EGF-induced ARO cell invasiveness through the reduction of Rho geranylgeranylation, which in turn suppressed the membrane translocation, and subsequent suppression of Rho/ROCK and FAK/paxillin signaling.
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Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis
Endocrinology, 2003Co-Authors: Wenbin Zhong, Chihyuan Wang, Tienchun Chang, Wen Sen LeeAbstract:Lovastatin has been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Inhibition of mevalonate synthesis may result in antiproliferation and cell apoptosis. The aim of the present study was to examine the apoptotic effect of Lovastatin in human ARO cells and delineate its underlying molecular mechanism. Our results showed that Lovastatin dose- and time-dependently induced apoptosis in ARO cells. Pretreatment with cycloheximide dose-dependently suppressed Lovastatin-induced apoptosis, suggesting that de novo protein synthesis is required for Lovastatin effect on the induction of apoptosis in ARO cells. Treatment of the cells with 50 microM Lovastatin induced cytochrome c translocation from mitochondria to cytosol; increases in caspase-2, -3, and -9 activity; and poly (ADP-ribose) polymerase degradation in a time-dependent manner. However, administration of mevalonate or geranylgeraniol, but not farnesol, dose-dependently prevented Lovastatin-induced poly (ADP-ribose) polymerase degradation and the occurrence of apoptosis, but treatment with geranylgeranyl transferase inhibitor, GGTI-298, which blocks the geranylgeranylation, induced an increase in the percentage of the apoptotic cells. These data suggest that geranylgeranylation is required for survival of the Lovastatin-treated ARO cells. To support this notion, we demonstrate that Lovastatin dose-dependently decreased the translocation of RhoA and Rac1, but not Ras, from cytosol to membrane fraction. Moreover, the Lovastatin-induced translocation inhibitions in RhoA and Rac1 were prevented by mevalonate and geranylgeraniol but not farnesol. In conclusion, our data suggest that Lovastatin induced apoptosis in ARO cells by inhibiting protein geranylgeranylation of the Rho family but not farnesylation of the Ras family.
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Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis
Endocrinology, 2003Co-Authors: Wenbin Zhong, Chihyuan Wang, Tienchun ChangAbstract:Lovastatin has been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Inhibition of mevalonate synthesis may result in antiproliferation and cell apoptosis. The aim of the present study was to examine the apoptotic effect of Lovastatin in human ARO cells and delineate its underlying molecular mechanism. Our results showed that Lovastatin dose- and time-dependently induced apoptosis in ARO cells. Pretreatment with cycloheximide dose-dependently suppressed Lovastatin-induced apoptosis, suggesting that de novo protein synthesis is required for Lovastatin effect on the induction of apoptosis in ARO cells. Treatment of the cells with 50 μm Lovastatin induced cytochrome c translocation from mitochondria to cytosol; increases in caspase-2, -3, and -9 activity; and poly (ADP-ribose) polymerase degradation in a time-dependent manner. However, administration of mevalonate or geranylgeraniol, but not farnesol, dose-dependently prevented Lovastatin-induced poly (ADP-ribose) poly...
Wen Sen Lee - One of the best experts on this subject based on the ideXlab platform.
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Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis
Endocrinology, 2003Co-Authors: Wenbin Zhong, Chihyuan Wang, Tienchun Chang, Wen Sen LeeAbstract:Lovastatin has been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Inhibition of mevalonate synthesis may result in antiproliferation and cell apoptosis. The aim of the present study was to examine the apoptotic effect of Lovastatin in human ARO cells and delineate its underlying molecular mechanism. Our results showed that Lovastatin dose- and time-dependently induced apoptosis in ARO cells. Pretreatment with cycloheximide dose-dependently suppressed Lovastatin-induced apoptosis, suggesting that de novo protein synthesis is required for Lovastatin effect on the induction of apoptosis in ARO cells. Treatment of the cells with 50 microM Lovastatin induced cytochrome c translocation from mitochondria to cytosol; increases in caspase-2, -3, and -9 activity; and poly (ADP-ribose) polymerase degradation in a time-dependent manner. However, administration of mevalonate or geranylgeraniol, but not farnesol, dose-dependently prevented Lovastatin-induced poly (ADP-ribose) polymerase degradation and the occurrence of apoptosis, but treatment with geranylgeranyl transferase inhibitor, GGTI-298, which blocks the geranylgeranylation, induced an increase in the percentage of the apoptotic cells. These data suggest that geranylgeranylation is required for survival of the Lovastatin-treated ARO cells. To support this notion, we demonstrate that Lovastatin dose-dependently decreased the translocation of RhoA and Rac1, but not Ras, from cytosol to membrane fraction. Moreover, the Lovastatin-induced translocation inhibitions in RhoA and Rac1 were prevented by mevalonate and geranylgeraniol but not farnesol. In conclusion, our data suggest that Lovastatin induced apoptosis in ARO cells by inhibiting protein geranylgeranylation of the Rho family but not farnesylation of the Ras family.
