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Christopher J Gorski - One of the best experts on this subject based on the ideXlab platform.
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regioselective biotransformation of midazolam by members of the human cytochrome p450 3a cyp3a subfamily
Biochemical Pharmacology, 1994Co-Authors: Stephen D. Hall, Christopher J Gorski, David R Jones, Mark VandenbrandenAbstract:Abstract The capabilities of cytochrome P4503A4 (CYP3A4), CYP3A5, and fetal hepatic microsomes containing CYP3A7 to metabolize midazolam were investigated using human hepatic microsomes and purified CYP3A4 and CYP3A5. Under initial rate conditions and High Substrate Concentration (400 μM midazolam), variability among eighteen human liver microsomal samples was 30- and 16- fold for 1′- and 4-hydroxylation of midazolam, respectively. Exclusion of two samples isolated from patients previously administered barbiturates reduced the inter-individual variability to 10.5- and 6.0-fold for 1′- and 4-hydroxylation, respectively. Six fetal hepatic microsomal samples showed 10-fold variation in both 1′-hydroxymidazolam and 4-hydroxymidazolam formation rates. The rates of formation of 4-hydroxymidazolam and 1′-hydroxymidazolam from midazolam by adult samples containing only CYP3A4 and by fetal liver samples were Highly correlated ( r 2 =0.99 and 0.97, P r 2 =0.95 and 0.92, respectively), 6β-hydroxylate testosterone ( r 2 =0.96 and 0.96, respectively), and the CYP3A4 content of the samples ( r 2 =0.89 and 0.86, respectively). Microsomal samples containing CYP3A5 in addition to CYP3A4 exhibited a significantly greater ration of 1′-hydroxymidazolam to 4-hydroxymidazolan compared with samples containing only CYP3A4 or CYP3A7 (P b 5 , and NADPH-cytochrome P450 reductase, and an NADPH-regenerating system displayed a 2-fold greater rate of 1′-hydroxymidazolam formation and a similar rate of 4-hydroxymidazolam formation compared with a reconstituted system with CYP3A4. In conclusion, CYP3A4, CYP3A5, and fetal microsomes containing CYP3A7 catalyze 1′- and 4-hydroxylation of midazolam with the ratio of these metabolites indicative of the CYP3A form.
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regioselective biotransformation of midazolam by members of the human cytochrome p450 3a cyp3a subfamily
Biochemical Pharmacology, 1994Co-Authors: Stephen D. Hall, Christopher J Gorski, David R Jones, Mark VandenbrandenAbstract:The capabilities of cytochrome P4503A4 (CYP3A4), CYP3A5, and fetal hepatic microsomes containing CYP3A7 to metabolize midazolam were investigated using human hepatic microsomes and purified CYP3A4 and CYP3A5. Under initial rate conditions and High Substrate Concentration (400 microM midazolam), variability among eighteen human liver microsomal samples was 30- and 16- fold for 1'- and 4-hydroxylation of midazolam, respectively. Exclusion of two samples isolated from patients previously administered barbiturates reduced the inter-individual variability to 10.5- and 6.0-fold for 1'- and 4-hydroxylation, respectively. Six fetal hepatic microsomal samples showed 10-fold variation in both 1'-hydroxymidazolam and 4-hydroxymidazolam formation rates. The rates of formation of 4-hydroxymidazolam and 1'-hydroxymidazolam from midazolam by adult samples containing only CYP3A4 and by fetal liver samples were Highly correlated (r2 = 0.99 and 0.97, P < 0.01, respectively). The rates of formation of 1'-hydroxymidazolam and 4-hydroxymidazolam from midazolam (400 microM) by adult samples that contained only CYP3A4 were correlated significantly (P < 0.01) with the ability of the samples to N-demethylate erythromycin (r2 = 0.95 and 0.92, respectively). 6 beta-hydroxylate testosterone (r2 = 0.96 and 0.96, respectively), and the CYP3A4 content of the samples (r2 = 0.89 and 0.86, respectively). Microsomal samples containing CYP3A5 in addition to CYP3A4 exhibited a significantly greater ratio of 1'-hydroxymidazolam to 4-hydroxymidazolam compared with samples containing only CYP3A4 or CYP3A7 (P < 0.001). Purified CYP3A5 in a reconstituted system, consisting of dilauroylphosphatidylcholine, cytochrome b5, and NADPH-cytochrome P450 reductase, and an NADPH-regenerating system displayed a 2-fold greater rate of 1'-hydroxymidazolam formation and a similar rate of 4-hydroxymidazolam formation compared with a reconstituted system with CYP3A4. In conclusion, CYP3A4, CYP3A5, and fetal microsomes containing CYP3A7 catalyze 1'- and 4-hydroxylation of midazolam with the ratio of these metabolites indicative of the CYP3A form.
Mark Vandenbranden - One of the best experts on this subject based on the ideXlab platform.
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regioselective biotransformation of midazolam by members of the human cytochrome p450 3a cyp3a subfamily
Biochemical Pharmacology, 1994Co-Authors: Stephen D. Hall, Christopher J Gorski, David R Jones, Mark VandenbrandenAbstract:Abstract The capabilities of cytochrome P4503A4 (CYP3A4), CYP3A5, and fetal hepatic microsomes containing CYP3A7 to metabolize midazolam were investigated using human hepatic microsomes and purified CYP3A4 and CYP3A5. Under initial rate conditions and High Substrate Concentration (400 μM midazolam), variability among eighteen human liver microsomal samples was 30- and 16- fold for 1′- and 4-hydroxylation of midazolam, respectively. Exclusion of two samples isolated from patients previously administered barbiturates reduced the inter-individual variability to 10.5- and 6.0-fold for 1′- and 4-hydroxylation, respectively. Six fetal hepatic microsomal samples showed 10-fold variation in both 1′-hydroxymidazolam and 4-hydroxymidazolam formation rates. The rates of formation of 4-hydroxymidazolam and 1′-hydroxymidazolam from midazolam by adult samples containing only CYP3A4 and by fetal liver samples were Highly correlated ( r 2 =0.99 and 0.97, P r 2 =0.95 and 0.92, respectively), 6β-hydroxylate testosterone ( r 2 =0.96 and 0.96, respectively), and the CYP3A4 content of the samples ( r 2 =0.89 and 0.86, respectively). Microsomal samples containing CYP3A5 in addition to CYP3A4 exhibited a significantly greater ration of 1′-hydroxymidazolam to 4-hydroxymidazolan compared with samples containing only CYP3A4 or CYP3A7 (P b 5 , and NADPH-cytochrome P450 reductase, and an NADPH-regenerating system displayed a 2-fold greater rate of 1′-hydroxymidazolam formation and a similar rate of 4-hydroxymidazolam formation compared with a reconstituted system with CYP3A4. In conclusion, CYP3A4, CYP3A5, and fetal microsomes containing CYP3A7 catalyze 1′- and 4-hydroxylation of midazolam with the ratio of these metabolites indicative of the CYP3A form.
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regioselective biotransformation of midazolam by members of the human cytochrome p450 3a cyp3a subfamily
Biochemical Pharmacology, 1994Co-Authors: Stephen D. Hall, Christopher J Gorski, David R Jones, Mark VandenbrandenAbstract:The capabilities of cytochrome P4503A4 (CYP3A4), CYP3A5, and fetal hepatic microsomes containing CYP3A7 to metabolize midazolam were investigated using human hepatic microsomes and purified CYP3A4 and CYP3A5. Under initial rate conditions and High Substrate Concentration (400 microM midazolam), variability among eighteen human liver microsomal samples was 30- and 16- fold for 1'- and 4-hydroxylation of midazolam, respectively. Exclusion of two samples isolated from patients previously administered barbiturates reduced the inter-individual variability to 10.5- and 6.0-fold for 1'- and 4-hydroxylation, respectively. Six fetal hepatic microsomal samples showed 10-fold variation in both 1'-hydroxymidazolam and 4-hydroxymidazolam formation rates. The rates of formation of 4-hydroxymidazolam and 1'-hydroxymidazolam from midazolam by adult samples containing only CYP3A4 and by fetal liver samples were Highly correlated (r2 = 0.99 and 0.97, P < 0.01, respectively). The rates of formation of 1'-hydroxymidazolam and 4-hydroxymidazolam from midazolam (400 microM) by adult samples that contained only CYP3A4 were correlated significantly (P < 0.01) with the ability of the samples to N-demethylate erythromycin (r2 = 0.95 and 0.92, respectively). 6 beta-hydroxylate testosterone (r2 = 0.96 and 0.96, respectively), and the CYP3A4 content of the samples (r2 = 0.89 and 0.86, respectively). Microsomal samples containing CYP3A5 in addition to CYP3A4 exhibited a significantly greater ratio of 1'-hydroxymidazolam to 4-hydroxymidazolam compared with samples containing only CYP3A4 or CYP3A7 (P < 0.001). Purified CYP3A5 in a reconstituted system, consisting of dilauroylphosphatidylcholine, cytochrome b5, and NADPH-cytochrome P450 reductase, and an NADPH-regenerating system displayed a 2-fold greater rate of 1'-hydroxymidazolam formation and a similar rate of 4-hydroxymidazolam formation compared with a reconstituted system with CYP3A4. In conclusion, CYP3A4, CYP3A5, and fetal microsomes containing CYP3A7 catalyze 1'- and 4-hydroxylation of midazolam with the ratio of these metabolites indicative of the CYP3A form.
Yu-guo Zheng - One of the best experts on this subject based on the ideXlab platform.
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large scale synthesis of tert butyl 3r 5s 6 chloro 3 5 dihydroxyhexanoate by a stereoselective carbonyl reductase with High Substrate Concentration and product yield
Biotechnology Progress, 2017Co-Authors: Zhi-qiang Liu, Ya-ping Xue, Xiaojian Zhang, Xiaoling Tang, Feng Cheng, Yajun Wang, Dankai Yao, Yiteng Zhou, Yu-guo ZhengAbstract:To biosynthesize the (3R,5S)-CDHH in an industrial scale, a newly synthesized stereoselective short chain carbonyl reductase (SCR) was successfully cloned and expressed in Escherichia coli. The fermentation of recombinant E. coli harboring SCR was carried out in 500 L and 5000 L fermenters, with biomass and specific activity of 9.7 g DCW/L, 15749.95 U/g DCW, and 10.97 g DCW/L, 19210.12 U/g DCW, respectively. The recombinant SCR was successfully applied for efficient production of (3R,5S)-CDHH. The scale-up synthesis of (3R,5S)-CDHH was performed in 5000 L bioreactor with 400 g/L of (S)-CHOH at 30°C, resulting in a space-time yield of 13.7 mM/h/g DCW, which was the Highest ever reported. After isolation and purification, the yield and d.e. of (3R,5S)-CDHH reached 97.5% and 99.5%, respectively. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:612-620, 2017.
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Efficient two-step chemo-enzymatic synthesis of all- trans -retinyl palmitate with High Substrate Concentration and product yield
Applied microbiology and biotechnology, 2015Co-Authors: Zhi-qiang Liu, Ling-mei Zhou, Peng Liu, Peter James Baker, Shan-shan Liu, Ya-ping Xue, Yu-guo ZhengAbstract:A new two-step chemo-enzymatic approach for Highly efficient synthesis of all-trans-retinyl palmitate is constructed in this study. In the first step, retinyl acetate as starting material was fully hydrolyzed to retinol by potassium hydroxide. In the hydrolysis system, anhydrous ethanol was the best co-solvent to increase the solubility of retinyl acetate. The addition amounts of 5 M potassium hydroxide and anhydrous ethanol were 8 and 10 mL against 10 g retinyl acetate, respectively, and 100 % hydrolysis rate was obtained. In the second step, esterification was catalyzed by immobilized lipase on macroporous acrylic resin AB-8 using the extracted retinol and palmitic acid as Substrates in non-aqueous system. After optimization, the parameters of esterification reaction were confirmed as follows: non-aqueous solvent was selected as n-hexane, washing times of extraction solution was four times, retinol Concentration was 300 g/L, Substrate molar ratio of retinol to palmitic acid was 1:1.1, the amount of immobilized enzyme was 10 g/L, and the esterification temperature was 30 °C. Under the optimal conditions, this protocol resulted in a 97.5 % yield of all-trans-retinyl palmitate in 700-L reactor. After purification, all-trans-retinyl palmitate was obtained with above 99 % of purity and 88 % of total recovery rate. This methodology provides a promising strategy for the large-scale production of all-trans-retinyl palmitate.
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biosynthesis of r epichlorohydrin at High Substrate Concentration by kinetic resolution of racemic epichlorohydrin with a recombinant epoxide hydrolase
Engineering in Life Sciences, 2013Co-Authors: Huoxi Jin, Zhi-qiang Liu, Yu-guo ZhengAbstract:The Substrate Concentration and yield were shown to be very low in the production of (R)-epichlorohydrin by hydrolysis of racemic epichlorohydrin using epoxide hydrolases in previous studies. In this work, we synthesized an epoxide hydrolase gene from Agrobacterium radiobacter and expressed it in Escherichia coli by the PCR assembly method. The recombinant A. radiobacter epoxide hydrolase (ArEH) was applied in the preparation of (R)-epichlorohydrin and, a yield of 42.7% with ≥99% enantiomeric excess (ee) from 25.6 mM racemic epichlorohydrin was obtained. However, the ee of (R)-epichlorohydrin was not able to reach 99% due to Substrate and product inhibition when the Substrate Concentration was over 320 mM. Inhibition studies revealed that (S)-3-chloro-1,2-propanediol displayed non-competitive inhibition in the conversion of (S)-epichlorohydrin but non-significant inhibition for (R)-epichlorohydrin. Moreover, ArEH was successfully applied in the preparation of (R)-epichlorohydrin at High Substrate Concentration by eliminating the Substrate inhibition. The Substrate Concentration increased to 448 mM by intermittent feeding of the Substrate and to 512 mM by using a two-phase reaction system, with a High yield (>27%) and ee (>98%) of (R)-epichlorohydrin. This is the first report of High-yield production of (R)-epichlorohydrin at High Substrate Concentration, laying the foundations for its application on the industrial scale.
Chiehfu Chen - One of the best experts on this subject based on the ideXlab platform.
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oxidative metabolism of the alkaloid rutaecarpine by human cytochrome p450
Drug Metabolism and Disposition, 2006Co-Authors: Yune-fang Ueng, Li Kang Ho, Shuyun Wang, Chiehfu ChenAbstract:Rutaecarpine is the main active alkaloid of the herbal medicine, Evodia rutaecarpa . To identify the major human cytochrome P450 (P450) participating in rutaecarpine oxidative metabolism, human liver microsomes and bacteria-expressed recombinant human P450 were studied. In liver microsomes, rutaecarpine was oxidized to 10-, 11-, 12-, and 3-hydroxyrutaecarpine. Microsomal 10- and 3-hydroxylation activities were strongly inhibited by ketoconazole. The 11- and 12-hydroxylation activities were inhibited by α-naphthoflavone, quinidine, and ketoconazole. These results indicated that multiple hepatic P450s including CYP1A2, CYP2D6, and CYP3A4 participate in rutaecarpine hydroxylations. Among recombinant P450s, CYP1A1 had the Highest rutaecarpine hydroxylation activity. Decreased metabolite formation at High Substrate Concentration indicated that there was Substrate inhibition of CYP1A1- and CYP1A2-catalyzed hydroxylations. CYP1A1-catalyzed rutaecarpine hydroxylations had V max values of 1388 to ∼1893 pmol/min/nmol P450, K m values of 4.1 to ∼9.5 μM, and K i values of 45 to ∼103 μM. These results indicated that more than one molecule of rutaecarpine is accessible to the CYP1A active site. The major metabolite 10-hydroxyrutaecarpine decreased CYP1A1, CYP1A2, and CYP1B1 activities with respective IC 50 values of 2.56 ± 0.04, 2.57 ± 0.11, and 0.09 ± 0.01 μM, suggesting that product inhibition might occur during rutaecarpine hydroxylation. The metabolite profile and kinetic properties of rutaecarpine hydroxylation by human P450s provide important information relevant to the clinical application of rutaecarpine and E. rutaecarpa .
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oxidative metabolism of the alkaloid rutaecarpine by human cytochrome p450
Drug Metabolism and Disposition, 2006Co-Authors: Yune-fang Ueng, Li Kang Ho, Shuyun Wang, Chiehfu ChenAbstract:Rutaecarpine is the main active alkaloid of the herbal medicine, Evodia rutaecarpa . To identify the major human cytochrome P450 (P450) participating in rutaecarpine oxidative metabolism, human liver microsomes and bacteria-expressed recombinant human P450 were studied. In liver microsomes, rutaecarpine was oxidized to 10-, 11-, 12-, and 3-hydroxyrutaecarpine. Microsomal 10- and 3-hydroxylation activities were strongly inhibited by ketoconazole. The 11- and 12-hydroxylation activities were inhibited by α-naphthoflavone, quinidine, and ketoconazole. These results indicated that multiple hepatic P450s including CYP1A2, CYP2D6, and CYP3A4 participate in rutaecarpine hydroxylations. Among recombinant P450s, CYP1A1 had the Highest rutaecarpine hydroxylation activity. Decreased metabolite formation at High Substrate Concentration indicated that there was Substrate inhibition of CYP1A1- and CYP1A2-catalyzed hydroxylations. CYP1A1-catalyzed rutaecarpine hydroxylations had V max values of 1388 to ∼1893 pmol/min/nmol P450, K m values of 4.1 to ∼9.5 μM, and K i values of 45 to ∼103 μM. These results indicated that more than one molecule of rutaecarpine is accessible to the CYP1A active site. The major metabolite 10-hydroxyrutaecarpine decreased CYP1A1, CYP1A2, and CYP1B1 activities with respective IC 50 values of 2.56 ± 0.04, 2.57 ± 0.11, and 0.09 ± 0.01 μM, suggesting that product inhibition might occur during rutaecarpine hydroxylation. The metabolite profile and kinetic properties of rutaecarpine hydroxylation by human P450s provide important information relevant to the clinical application of rutaecarpine and E. rutaecarpa .
Stephen D. Hall - One of the best experts on this subject based on the ideXlab platform.
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regioselective biotransformation of midazolam by members of the human cytochrome p450 3a cyp3a subfamily
Biochemical Pharmacology, 1994Co-Authors: Stephen D. Hall, Christopher J Gorski, David R Jones, Mark VandenbrandenAbstract:Abstract The capabilities of cytochrome P4503A4 (CYP3A4), CYP3A5, and fetal hepatic microsomes containing CYP3A7 to metabolize midazolam were investigated using human hepatic microsomes and purified CYP3A4 and CYP3A5. Under initial rate conditions and High Substrate Concentration (400 μM midazolam), variability among eighteen human liver microsomal samples was 30- and 16- fold for 1′- and 4-hydroxylation of midazolam, respectively. Exclusion of two samples isolated from patients previously administered barbiturates reduced the inter-individual variability to 10.5- and 6.0-fold for 1′- and 4-hydroxylation, respectively. Six fetal hepatic microsomal samples showed 10-fold variation in both 1′-hydroxymidazolam and 4-hydroxymidazolam formation rates. The rates of formation of 4-hydroxymidazolam and 1′-hydroxymidazolam from midazolam by adult samples containing only CYP3A4 and by fetal liver samples were Highly correlated ( r 2 =0.99 and 0.97, P r 2 =0.95 and 0.92, respectively), 6β-hydroxylate testosterone ( r 2 =0.96 and 0.96, respectively), and the CYP3A4 content of the samples ( r 2 =0.89 and 0.86, respectively). Microsomal samples containing CYP3A5 in addition to CYP3A4 exhibited a significantly greater ration of 1′-hydroxymidazolam to 4-hydroxymidazolan compared with samples containing only CYP3A4 or CYP3A7 (P b 5 , and NADPH-cytochrome P450 reductase, and an NADPH-regenerating system displayed a 2-fold greater rate of 1′-hydroxymidazolam formation and a similar rate of 4-hydroxymidazolam formation compared with a reconstituted system with CYP3A4. In conclusion, CYP3A4, CYP3A5, and fetal microsomes containing CYP3A7 catalyze 1′- and 4-hydroxylation of midazolam with the ratio of these metabolites indicative of the CYP3A form.
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regioselective biotransformation of midazolam by members of the human cytochrome p450 3a cyp3a subfamily
Biochemical Pharmacology, 1994Co-Authors: Stephen D. Hall, Christopher J Gorski, David R Jones, Mark VandenbrandenAbstract:The capabilities of cytochrome P4503A4 (CYP3A4), CYP3A5, and fetal hepatic microsomes containing CYP3A7 to metabolize midazolam were investigated using human hepatic microsomes and purified CYP3A4 and CYP3A5. Under initial rate conditions and High Substrate Concentration (400 microM midazolam), variability among eighteen human liver microsomal samples was 30- and 16- fold for 1'- and 4-hydroxylation of midazolam, respectively. Exclusion of two samples isolated from patients previously administered barbiturates reduced the inter-individual variability to 10.5- and 6.0-fold for 1'- and 4-hydroxylation, respectively. Six fetal hepatic microsomal samples showed 10-fold variation in both 1'-hydroxymidazolam and 4-hydroxymidazolam formation rates. The rates of formation of 4-hydroxymidazolam and 1'-hydroxymidazolam from midazolam by adult samples containing only CYP3A4 and by fetal liver samples were Highly correlated (r2 = 0.99 and 0.97, P < 0.01, respectively). The rates of formation of 1'-hydroxymidazolam and 4-hydroxymidazolam from midazolam (400 microM) by adult samples that contained only CYP3A4 were correlated significantly (P < 0.01) with the ability of the samples to N-demethylate erythromycin (r2 = 0.95 and 0.92, respectively). 6 beta-hydroxylate testosterone (r2 = 0.96 and 0.96, respectively), and the CYP3A4 content of the samples (r2 = 0.89 and 0.86, respectively). Microsomal samples containing CYP3A5 in addition to CYP3A4 exhibited a significantly greater ratio of 1'-hydroxymidazolam to 4-hydroxymidazolam compared with samples containing only CYP3A4 or CYP3A7 (P < 0.001). Purified CYP3A5 in a reconstituted system, consisting of dilauroylphosphatidylcholine, cytochrome b5, and NADPH-cytochrome P450 reductase, and an NADPH-regenerating system displayed a 2-fold greater rate of 1'-hydroxymidazolam formation and a similar rate of 4-hydroxymidazolam formation compared with a reconstituted system with CYP3A4. In conclusion, CYP3A4, CYP3A5, and fetal microsomes containing CYP3A7 catalyze 1'- and 4-hydroxylation of midazolam with the ratio of these metabolites indicative of the CYP3A form.