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Rhonda M. Brand - One of the best experts on this subject based on the ideXlab platform.
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Transdermal Use of Phosphorodiamidate Morpholino Oligomer AVI-4472 Inhibits Cytochrome P450 3A2 Activity in Male Rats
Pharmaceutical Research, 2002Co-Authors: Vikram Arora, Patrick L. Iversen, Tracy L. Hannah, Rhonda M. BrandAbstract:Purpose . To determine if dermal absorption of an antisense phosphorodiamidate Morpholino oligomers (PMO) can inhibit target gene expression in the liver in vivo . Method . Antisense PMO targeted to Cytochrome P450 (CYP) 3A2 was applied topically to adult male rats at doses of 0.03, 0.3, and 3.0 mg. CYP3A enzyme activity in the underlying skin and liver was evaluated 24 h following application. Results . Systemic PMO bioavailability was determined by detection of full-length PMO in liver and fluorescence micrography in underlying skin. CYP3A enzyme activity were measured by hydroxylation of 7-benzyloxy-4-(trifluoromethyl)-coumarin and data were expressed as nanomoles of product/ 100 μg S9 protein/h. A topical dose of 0.03 mg inhibited enzyme levels from 576 ± 17 (vehicle) and 564 ± 20 (control PMO) to 432 ± 20 in the antisense-treated liver (p < 0.05). Increasing the dose to 0.3 mg further inhibited enzyme level to 278 ± 13 (p < 0.005). The inhibition did not increase further when the dose was increased to 3 mg. In the skin, starting enzyme levels were approximately one third of the liver (171 ± 9) and maximum inhibition was reached at a lower dose. Topical delivery of 0.03 mg led reduced skin enzyme levels in half to 89 ± 32 (p < 0.05). Increasing the dose to 0.3 mg and 3.0 mg did not produce any further inhibition, at 73 ± 8 and 72 ± 17 respectively. Conclusion . Topical application of antisense PMO in rats is a feasible delivery strategy for gene targets in liver and underlying skin.
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Transdermal use of phosphorodiamidate morpholino oligomer AVI-4472 inhibits Cytochrome P450 3A2 activity in male rats.
Pharmaceutical research, 2002Co-Authors: Vikram Arora, Patrick L. Iversen, Tracy L. Hannah, Rhonda M. BrandAbstract:Purpose. To determine if dermal absorption of an antisense phosphorodiamidate Morpholino oligomers (PMO) can inhibit target gene expression in the liver in vivo.
Vikram Arora - One of the best experts on this subject based on the ideXlab platform.
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Transdermal Use of Phosphorodiamidate Morpholino Oligomer AVI-4472 Inhibits Cytochrome P450 3A2 Activity in Male Rats
Pharmaceutical Research, 2002Co-Authors: Vikram Arora, Patrick L. Iversen, Tracy L. Hannah, Rhonda M. BrandAbstract:Purpose . To determine if dermal absorption of an antisense phosphorodiamidate Morpholino oligomers (PMO) can inhibit target gene expression in the liver in vivo . Method . Antisense PMO targeted to Cytochrome P450 (CYP) 3A2 was applied topically to adult male rats at doses of 0.03, 0.3, and 3.0 mg. CYP3A enzyme activity in the underlying skin and liver was evaluated 24 h following application. Results . Systemic PMO bioavailability was determined by detection of full-length PMO in liver and fluorescence micrography in underlying skin. CYP3A enzyme activity were measured by hydroxylation of 7-benzyloxy-4-(trifluoromethyl)-coumarin and data were expressed as nanomoles of product/ 100 μg S9 protein/h. A topical dose of 0.03 mg inhibited enzyme levels from 576 ± 17 (vehicle) and 564 ± 20 (control PMO) to 432 ± 20 in the antisense-treated liver (p < 0.05). Increasing the dose to 0.3 mg further inhibited enzyme level to 278 ± 13 (p < 0.005). The inhibition did not increase further when the dose was increased to 3 mg. In the skin, starting enzyme levels were approximately one third of the liver (171 ± 9) and maximum inhibition was reached at a lower dose. Topical delivery of 0.03 mg led reduced skin enzyme levels in half to 89 ± 32 (p < 0.05). Increasing the dose to 0.3 mg and 3.0 mg did not produce any further inhibition, at 73 ± 8 and 72 ± 17 respectively. Conclusion . Topical application of antisense PMO in rats is a feasible delivery strategy for gene targets in liver and underlying skin.
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Transdermal use of phosphorodiamidate morpholino oligomer AVI-4472 inhibits Cytochrome P450 3A2 activity in male rats.
Pharmaceutical research, 2002Co-Authors: Vikram Arora, Patrick L. Iversen, Tracy L. Hannah, Rhonda M. BrandAbstract:Purpose. To determine if dermal absorption of an antisense phosphorodiamidate Morpholino oligomers (PMO) can inhibit target gene expression in the liver in vivo.
Patrick L. Iversen - One of the best experts on this subject based on the ideXlab platform.
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Transdermal Use of Phosphorodiamidate Morpholino Oligomer AVI-4472 Inhibits Cytochrome P450 3A2 Activity in Male Rats
Pharmaceutical Research, 2002Co-Authors: Vikram Arora, Patrick L. Iversen, Tracy L. Hannah, Rhonda M. BrandAbstract:Purpose . To determine if dermal absorption of an antisense phosphorodiamidate Morpholino oligomers (PMO) can inhibit target gene expression in the liver in vivo . Method . Antisense PMO targeted to Cytochrome P450 (CYP) 3A2 was applied topically to adult male rats at doses of 0.03, 0.3, and 3.0 mg. CYP3A enzyme activity in the underlying skin and liver was evaluated 24 h following application. Results . Systemic PMO bioavailability was determined by detection of full-length PMO in liver and fluorescence micrography in underlying skin. CYP3A enzyme activity were measured by hydroxylation of 7-benzyloxy-4-(trifluoromethyl)-coumarin and data were expressed as nanomoles of product/ 100 μg S9 protein/h. A topical dose of 0.03 mg inhibited enzyme levels from 576 ± 17 (vehicle) and 564 ± 20 (control PMO) to 432 ± 20 in the antisense-treated liver (p < 0.05). Increasing the dose to 0.3 mg further inhibited enzyme level to 278 ± 13 (p < 0.005). The inhibition did not increase further when the dose was increased to 3 mg. In the skin, starting enzyme levels were approximately one third of the liver (171 ± 9) and maximum inhibition was reached at a lower dose. Topical delivery of 0.03 mg led reduced skin enzyme levels in half to 89 ± 32 (p < 0.05). Increasing the dose to 0.3 mg and 3.0 mg did not produce any further inhibition, at 73 ± 8 and 72 ± 17 respectively. Conclusion . Topical application of antisense PMO in rats is a feasible delivery strategy for gene targets in liver and underlying skin.
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Transdermal use of phosphorodiamidate morpholino oligomer AVI-4472 inhibits Cytochrome P450 3A2 activity in male rats.
Pharmaceutical research, 2002Co-Authors: Vikram Arora, Patrick L. Iversen, Tracy L. Hannah, Rhonda M. BrandAbstract:Purpose. To determine if dermal absorption of an antisense phosphorodiamidate Morpholino oligomers (PMO) can inhibit target gene expression in the liver in vivo.
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Inhibition of the rat Cytochrome P450 3A2 by an antisense phosphorothioate oligodeoxynucleotide in vivo.
The Journal of pharmacology and experimental therapeutics, 1995Co-Authors: J P Desjardins, Patrick L. IversenAbstract:CYP3A2 is one of the most abundantly expressed Cytochrome P450s (CYPs) in the rat liver and metabolizes numerous clinically important drugs. Studies were designed to examine efficacy, potency and specificity of antisense inhibition of CYP3A2 in vivo. Three phosphorothioate ODNs were used: 3A2-ATG, antisense to the CYP3A2 mRNA translational start site; 3A2-REV, 5' to 3' reverse sequence of 3A2-ATG; and C-MYC, antisense to the C-MYC mRNA translational start site. Midazolam (MZ) sleep times were used as CYP3A2-specific in vivo marker in male Sprague-Dawley rats. Administration of 1 mg/day 3A2-ATG for 2 days i.p. significantly increased MZ sleep times from 22.4 +/- 0.4 (saline) to 35.3 +/- 1.5 min. Administration of equivalent doses of noncomplementary 3A2-REV or C-MYC produced no significant changes in MZ sleep times (22.4 +/- 0.6 and 22.8 +/- 1.3, respectively). Liver microsomal erythromycin demethylase activity, a specific CYP3A2 assay, was significantly decreased from 124 +/- 13 mumol/mg per min in saline controls to 63.8 +/- 8 in 3A2-ATG-treated rats. Enzyme activities for CYPs 2E1, 1A1/2 and 2B1/2 were not significantly different between saline controls and 3A2-ATG-treated animals. The control ODNs 3A2-REV and C-MYC had no significant changes in enzymatic activities compared to saline. Western blot analysis revealed decreases in CYP3A2 protein but not CYP2B1 protein in 3A2-ATG rat microsomes compared to controls. These studies demonstrate for the first time that antisense ODNs can effectively, potently, and specifically inhibit CYP3A2 in vivo.
Tracy L. Hannah - One of the best experts on this subject based on the ideXlab platform.
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Transdermal Use of Phosphorodiamidate Morpholino Oligomer AVI-4472 Inhibits Cytochrome P450 3A2 Activity in Male Rats
Pharmaceutical Research, 2002Co-Authors: Vikram Arora, Patrick L. Iversen, Tracy L. Hannah, Rhonda M. BrandAbstract:Purpose . To determine if dermal absorption of an antisense phosphorodiamidate Morpholino oligomers (PMO) can inhibit target gene expression in the liver in vivo . Method . Antisense PMO targeted to Cytochrome P450 (CYP) 3A2 was applied topically to adult male rats at doses of 0.03, 0.3, and 3.0 mg. CYP3A enzyme activity in the underlying skin and liver was evaluated 24 h following application. Results . Systemic PMO bioavailability was determined by detection of full-length PMO in liver and fluorescence micrography in underlying skin. CYP3A enzyme activity were measured by hydroxylation of 7-benzyloxy-4-(trifluoromethyl)-coumarin and data were expressed as nanomoles of product/ 100 μg S9 protein/h. A topical dose of 0.03 mg inhibited enzyme levels from 576 ± 17 (vehicle) and 564 ± 20 (control PMO) to 432 ± 20 in the antisense-treated liver (p < 0.05). Increasing the dose to 0.3 mg further inhibited enzyme level to 278 ± 13 (p < 0.005). The inhibition did not increase further when the dose was increased to 3 mg. In the skin, starting enzyme levels were approximately one third of the liver (171 ± 9) and maximum inhibition was reached at a lower dose. Topical delivery of 0.03 mg led reduced skin enzyme levels in half to 89 ± 32 (p < 0.05). Increasing the dose to 0.3 mg and 3.0 mg did not produce any further inhibition, at 73 ± 8 and 72 ± 17 respectively. Conclusion . Topical application of antisense PMO in rats is a feasible delivery strategy for gene targets in liver and underlying skin.
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Transdermal use of phosphorodiamidate morpholino oligomer AVI-4472 inhibits Cytochrome P450 3A2 activity in male rats.
Pharmaceutical research, 2002Co-Authors: Vikram Arora, Patrick L. Iversen, Tracy L. Hannah, Rhonda M. BrandAbstract:Purpose. To determine if dermal absorption of an antisense phosphorodiamidate Morpholino oligomers (PMO) can inhibit target gene expression in the liver in vivo.
Hassan Malekinejad - One of the best experts on this subject based on the ideXlab platform.
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Atorvastatin up-regulates the expression and activity of renal Cytochrome P450 3A2 in diabetic rats
Journal of Applied Biomedicine, 2016Co-Authors: Hassan Malekinejad, Shahin Alizadeh-fanalou, Rahim Hobbenaghi, Shirin Rokhsartalb-azarAbstract:Effects of atorvastatin on the expression of Cytochrome P450 3A2 and its enzymatic activity in the kidney of diabetic rats were investigated. Diabetes was induced by injection of streptozotocine (50 mg/kg, b.w., i.p.) in male Wistar rats. The animals were assigned into four groups including control (C), non-treated diabetic (D), atorvastatin-treated diabetic (AD) and atorvastatin-treated non-diabetic (A) groups. Metabolism of testosterone was examined in the presence of renal microsomes. The expression of CYP 3A2 at mRNA level was examined by means of PCR technique. The atorvastatin administration resulted in a remarkable improvement of diabetes-induced nephropathy and oxidative stress. Enzyme kinetics analyses showed that both diabetic groups produced significantly (P < 0.05) more 6β-hydroxytestosterone (Vmax for D = 34.7 ± 1.3 and for AD = 45.1 ± 2.3 pM/min/mg) than that of the control group (Vmax = 21.6 ± 1.5 pM/min/mg). Both diabetes and atorvastatin administration resulted in a significant up regulation of CYP 3A2 mRNA level in the kidney. Our data suggest that due to profound influence of diabetes and atorvastatin on renal metabolism of CYP 3A2 substrate and up-regulation of this gene, there should be adjusted dose regimen for medications which are classified as CYP 3A2 substrates.
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Silymarin regulates the Cytochrome P450 3A2 and glutathione peroxides in the liver of streptozotocin-induced diabetic rats.
Phytomedicine : international journal of phytotherapy and phytopharmacology, 2012Co-Authors: Hassan Malekinejad, Aysa Rezabakhsh, Fatemeh Rahmani, R. HobbenaghiAbstract:Abstract This study aimed to investigate the protective and regulatory effects of silymarin (SMN) and melatonin (MEL) on streptozotocin (STZ)-induced diabetic changes in Cytochrome P450 3A2 (CYP 3A2) and glutathione peroxidase (GPX) expression and antioxidant status in the liver. Male Wistar rats were divided into five groups, including: control (C), untreated diabetic animals (D), SMN-treated diabetics (S, 50 mg/kg, orally), MEL-treated diabetics (M, 10 mg/kg, i.p.), and SMN plus MEL-treated diabetics (S + M). Diabetes was induced by a single intraperitoneal injection of STZ (50 mg/kg). The blood glucose level, daily urinary volume and body weight changes were measured. After the 28 days treatment period, antioxidant status was analyzed by means of the determination of malondialdehyde (MDA) content, nitric oxide (NO) and total thiol molecules (TTM) levels in the liver. The glycogen depletion in the liver was examined by histochemical staining. The CYP 3A2 and GPX expression at mRNA level was determined using RT-PCT technique. SMN and MEL both individually or in combination prevented from diabetes-induced weight loss and lowered daily urinary volume significantly ( p p > 0.05). Both SMN and MEL could convert the diabetes induced elevated levels of MDA and NO and the diabetes-reduced TTM content to the control level. Moreover, the diabetes-up regulated CYP 3A2 and down regulated GPX, returned to normal values after SMN treatment. Histochemical and histopathological examinations revealed that the diabetes-induced glycogen-depletion and single cell necrosis markedly improved with the SMN and SMN plus MEL treatment. Our data suggest that the STZ-induced diabetes in addition of disturbing the antioxidant status, alters the expression levels of CYP 3A2 and GPX. Moreover, the SMN and SMN plus MEL treatment was able to normalize both the antioxidant status and the expression of CYP 3A2 and GPX in the liver of diabetic rats.
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Influences of sub-acute exposure to paraquat on Cytochrome P450 3A2 expression in rat liver and lungs
Pesticide Biochemistry and Physiology, 2010Co-Authors: Hassan Malekinejad, F. Rahmani, F. HassanpourAbstract:This study was designed to investigate the possible effects of paraquat sub-acute poisoning on Cytochrome P450 3A2 expression in the liver and lungs. Twenty adult male rats (150–200 g) were exposed either against saline normal as control group or various doses of paraquat (3.5, 7 and 10 mg/kg, s.c.) as test groups for 7 consecutive days. Paraquat-exposed animals showed loss of body weight and elevation in serum levels of alkaline phosphates and alanine aminotransferase in a dose-dependent fashion. Moreover, animals in the test groups demonstrated a significant (P < 0.05) increase of malondialdehyde content in both the liver and lung tissues. Ultimately, by using RT-PCR method it became clear that 7 days exposure to paraquat resulted in a total suppression of Cytochrome P450 3A2 at the mRNA level in the lungs. By contrast, a considerable up regulation of the same gene occurred in the liver. This data suggest that paraquat not only affect the lungs as a main target tissue but also up regulates the predominant Cytochrome P450 gene in the liver which may induce detoxification processes.
