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Shunichi Fukuzumi - One of the best experts on this subject based on the ideXlab platform.
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unified view of oxidative c h bond cleavage and Sulfoxidation by a nonheme iron iv oxo complex via lewis acid promoted electron transfer
Inorganic Chemistry, 2014Co-Authors: Jiyun Park, Wonwoo Nam, Yuma Morimoto, Yongmin Lee, Shunichi FukuzumiAbstract:Oxidative C–H bond cleavage of toluene derivatives and Sulfoxidation of thioanisole derivatives by a nonheme iron(IV)–oxo complex, [(N4Py)FeIV(O)]2+ (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine), were remarkably enhanced by the presence of triflic acid (HOTf) and Sc(OTf)3 in acetonitrile at 298 K. All the logarithms of the observed second-order rate constants of both the oxidative C–H bond cleavage and Sulfoxidation reactions exhibit remarkably unified correlations with the driving forces of proton-coupled electron transfer (PCET) and metal ion-coupled electron transfer (MCET) in light of the Marcus theory of electron transfer when the differences in the formation constants of precursor complexes between PCET and MCET were taken into account, respectively. Thus, the mechanisms of both the oxidative C–H bond cleavage of toluene derivatives and Sulfoxidation of thioanisole derivatives by [(N4Py)FeIV(O)]2+ in the presence of HOTf and Sc(OTf)3 have been unified as the rate-determining electron...
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proton promoted oxygen atom transfer vs proton coupled electron transfer of a non heme iron iv oxo complex
Journal of the American Chemical Society, 2012Co-Authors: Jiyun Park, Wonwoo Nam, Yuma Morimoto, Yongmin Lee, Shunichi FukuzumiAbstract:Sulfoxidation of thioanisoles by a non-heme iron(IV)–oxo complex, [(N4Py)FeIV(O)]2+ (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine), was remarkably enhanced by perchloric acid (70% HClO4). The observed second-order rate constant (kobs) of Sulfoxidation of thioaniosoles by [(N4Py)FeIV(O)]2+ increases linearly with increasing concentration of HClO4 (70%) in acetonitrile (MeCN)at 298 K. In contrast to Sulfoxidation of thioanisoles by [(N4Py)FeIV(O)]2+, the observed second-order rate constant (ket) of electron transfer from one-electron reductants such as [FeII(Me2bpy)3]2+ (Me2bpy = 4,4-dimehtyl-2,2′-bipyridine) to [(N4Py)FeIV(O)]2+ increases with increasing concentration of HClO4, exhibiting second-order dependence on HClO4 concentration. This indicates that the proton-coupled electron transfer (PCET) involves two protons associated with electron transfer from [FeII(Me2bpy)3]2+ to [(N4Py)FeIV(O)]2+ to yield [FeIII(Me2bpy)3]3+ and [(N4Py)FeIII(OH2)]3+. The one-electron reduction potential (Ered)...
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metal ion effect on the switch of mechanism from direct oxygen transfer to metal ion coupled electron transfer in the Sulfoxidation of thioanisoles by a non heme iron iv oxo complex
Journal of the American Chemical Society, 2011Co-Authors: Jiyun Park, Wonwoo Nam, Yuma Morimoto, Yongmin Lee, Shunichi FukuzumiAbstract:The mechanism of Sulfoxidation of thioaniosoles by a non-heme iron(IV)−oxo complex is switched from direct oxygen transfer to metal ion-coupled electron transfer by the presence of Sc3+. The switch in the Sulfoxidation mechanism is dependent on the one-electron oxidation potentials of thioanisoles. The rate of Sulfoxidation is accelerated as much as 102-fold by the addition of Sc3+.
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mechanisms of Sulfoxidation catalyzed by high valent intermediates of heme enzymes electron transfer vs oxygen transfer mechanism
Journal of the American Chemical Society, 1999Co-Authors: Yoshio Goto, Toshitaka Matsui, Shinichi Ozaki, Yoshihito Watanabe, Shunichi FukuzumiAbstract:Mechanisms of Sulfoxidation catalyzed by high-valent intermediates of heme enzymes have been investigated by direct observation of sulfide-induced reduction of three different compound I species including HRP (horseradish peroxidase), the His64Ser myoglobin (Mb) mutant, and OFeIVTMP+• (1) (TMP = 5,10,15,20-tetramesitylporphyrin dianion). The reaction of thioanisole and compound I of HRP (10 μM, pH 7.0, 298 K) gives the resting state of HRP with accumulation of compound II as an intermediate. The yield of sulfoxide by a stoichiometric reaction of HRP compound I with thioanisole was only 25% ± 5%. On the other hand, the same Sulfoxidation by both 1 and His64Ser Mb compound I exclusively exhibited a two-electron process, resulting in quantitative formation of sulfoxide. When 1,5-dithiacyclooctane (DTCO) is employed as a substrate, the reaction of His64Ser Mb compound I with DTCO exhibits rapid formation of compound II, which decays to the ferric state due to the low oxidation potential of DTCO. The observed ...
Manfred T Reetz - One of the best experts on this subject based on the ideXlab platform.
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p450 bm3 catalyzed Sulfoxidation versus hydroxylation a common or two different catalytically active species
Journal of the American Chemical Society, 2020Co-Authors: Jianbo Wang, Binju Wang, Bo Chen, Qun Huang, Wei Peng, Manfred T ReetzAbstract:While the mechanism of the P450-catalyzed oxidative hydroxylation of organic compounds has been studied in detail for many years, less is known about Sulfoxidation. Depending upon the structure of the respective substrate, heme-Fe═O (Cpd I), heme-Fe(III)-OOH (Cpd 0), and heme-Fe(III)-H2O2 (protonated Cpd 0) have been proposed as reactive intermediates. In the present study, we consider the transformation of isosteric substrates via Sulfoxidation and oxidative hydroxylation, respectively, catalyzed by regio- and enantioselective mutants of P450-BM3 which were constructed by directed evolution. 1-Thiochromanone and 1-tetralone were used as the isosteric substrates because, unlike previous studies involving fully flexible compounds such as thia-fatty acids and fatty acids, respectively, these compounds are rigid and cannot occur in a multitude of different conformations and binding modes in the large P450-BM3 binding pocket. The experimental results comprising activity and regio- and enantioselectivity, flanked by molecular dynamics computations within a time scale of 300 ns and QM/MM calculations of transition-state energies, unequivocally show that heme-Fe═O (Cpd I) is the common catalytically active intermediate in both Sulfoxidation and oxidative hydroxylation.
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chemo and stereoselective cytochrome p450 bm3 catalyzed Sulfoxidation of 1 thiochroman 4 ones enabled by directed evolution
Advanced Synthesis & Catalysis, 2017Co-Authors: Jianbo Wang, Manfred T Reetz, Adriana IlieAbstract:Directed evolution utilizing an unconventional approach to saturation mutagenesis has been applied to cytochrome P450-BM3 as a catalyst in the asymmetric Sulfoxidation of 1-thiochroman-4-one and two derivatives thereof with complete chemoselectivity as well as (S)- and (R)-selectivity on an optional basis. Whereas wild-type P450-BM3 shows in the case of the parent compound poor enantioselectivity in slight favor of the (S)-sulfoxide (er=75:25), (S)-selectivity was enhanced to er=93:7, while reversal of enantioselectivity favoring the (R)-sulfoxide was also achieved (er=7:93). Two derivatives of the parent substrate underwent similar stereoselective Sulfoxidation reactions. Sulfoxides of this type are of potential pharmaceutical interest. This biocatalytic approach nicely complements synthetic methods.
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extreme synergistic mutational effects in the directed evolution of a baeyer villiger monooxygenase as catalyst for asymmetric Sulfoxidation
Journal of the American Chemical Society, 2014Co-Authors: Manfred T Reetz, Zhigang Zhang, Richard Londsdale, Joaquin SanchismartinezAbstract:Structure-based directed evolution utilizing iterative saturation mutagenesis (ISM) has been applied to phenyl acetone monooxygenase (PAMO), a thermally robust Baeyer–Villiger monooxygenase, in the quest to access a mutant which displays reversed enantioselectivity in the asymmetric Sulfoxidation of prochiral thioethers. Whereas WT PAMO leads to 90% ee in the Sulfoxidation of p-methylbenzyl methyl thioether with preference for the (S)-sulfoxide, the evolved mutant I67Q/P440F/A442N/L443I is 95% (R)-selective in the reaction of this and other thioethers. Partial deconvolution of the (R)-selective mutant with generation of the respective four single mutants shows that all of them are (S)-selective, which points to pronounced synergism (cooperative nonadditivity) when they interact in concert. Complete deconvolution with formation of all combinatorial forms of the respective double and triple mutants allows the designed construction of a fitness landscape featuring all 24 upward pathways leading from WT to th...
Wonwoo Nam - One of the best experts on this subject based on the ideXlab platform.
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unified view of oxidative c h bond cleavage and Sulfoxidation by a nonheme iron iv oxo complex via lewis acid promoted electron transfer
Inorganic Chemistry, 2014Co-Authors: Jiyun Park, Wonwoo Nam, Yuma Morimoto, Yongmin Lee, Shunichi FukuzumiAbstract:Oxidative C–H bond cleavage of toluene derivatives and Sulfoxidation of thioanisole derivatives by a nonheme iron(IV)–oxo complex, [(N4Py)FeIV(O)]2+ (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine), were remarkably enhanced by the presence of triflic acid (HOTf) and Sc(OTf)3 in acetonitrile at 298 K. All the logarithms of the observed second-order rate constants of both the oxidative C–H bond cleavage and Sulfoxidation reactions exhibit remarkably unified correlations with the driving forces of proton-coupled electron transfer (PCET) and metal ion-coupled electron transfer (MCET) in light of the Marcus theory of electron transfer when the differences in the formation constants of precursor complexes between PCET and MCET were taken into account, respectively. Thus, the mechanisms of both the oxidative C–H bond cleavage of toluene derivatives and Sulfoxidation of thioanisole derivatives by [(N4Py)FeIV(O)]2+ in the presence of HOTf and Sc(OTf)3 have been unified as the rate-determining electron...
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the feiii h2o2 complex as a highly efficient oxidant in Sulfoxidation reactions revival of an underrated oxidant in cytochrome p450
Journal of Chemical Theory and Computation, 2013Co-Authors: Binju Wang, Wonwoo Nam, Kyungbin Cho, Sason ShaikAbstract:This work demonstrates that the FeIII(H2O2) complex, which has been considered as an unlikely oxidant in P450, is actually very efficient in Sulfoxidation reactions. Thus, FeIII(H2O2) undergoes a low-barrier nucleophilic attack by sulfur on the distal oxygen, resulting in heterolytic O–O cleavage coupled to proton transfer. We further show that FeIII(H2O2) is an efficient Sulfoxidation catalyst in synthetic iron porphyrin and iron corrolazine compounds. In all cases, FeIII(H2O2) performs the oxidation much faster than it converts to Cpd I and will therefore bypass Cpd I in the presence of a thioether. Thus, this paper not only suggests a plausible resolution of a longstanding issue in P450 chemistry regarding the “second oxidant” but also highlights a new mechanistic pathway for Sulfoxidation reactions in P450s and their multitude of synthetic analogues. These findings have far-reaching implications for transition metal compounds, where H2O2 is used as the terminal oxidant.
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a chromium iii superoxo complex in oxygen atom transfer reactions as a chemical model of cysteine dioxygenase
Journal of the American Chemical Society, 2012Co-Authors: Jaeheung Cho, Jaeyoung Woo, Wonwoo NamAbstract:Metal–superoxo species are believed to play key roles in oxygenation reactions by metalloenzymes. One example is cysteine dioxygenase (CDO) that catalyzes the oxidation of cysteine with O2, and an iron(III)–superoxo species is proposed as an intermediate that effects the Sulfoxidation reaction. We now report the first biomimetic example showing that a chromium(III)–superoxo complex bearing a macrocyclic TMC ligand, [CrIII(O2)(TMC)(Cl)]+, is an active oxidant in oxygen atom transfer (OAT) reactions, such as the oxidation of phosphine and sulfides. The electrophilic character of the Cr(III)–superoxo complex is demonstrated unambiguously in the Sulfoxidation of para-substituted thioanisoles. A Cr(IV)–oxo complex, [CrIV(O)(TMC)(Cl)]+, formed in the OAT reactions by the chromium(III)–superoxo complex, is characterized by X-ray crystallography and various spectroscopic methods. The present results support the proposed oxidant and mechanism in CDO, such as an iron(III)–superoxo species is an active oxidant that ...
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proton promoted oxygen atom transfer vs proton coupled electron transfer of a non heme iron iv oxo complex
Journal of the American Chemical Society, 2012Co-Authors: Jiyun Park, Wonwoo Nam, Yuma Morimoto, Yongmin Lee, Shunichi FukuzumiAbstract:Sulfoxidation of thioanisoles by a non-heme iron(IV)–oxo complex, [(N4Py)FeIV(O)]2+ (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine), was remarkably enhanced by perchloric acid (70% HClO4). The observed second-order rate constant (kobs) of Sulfoxidation of thioaniosoles by [(N4Py)FeIV(O)]2+ increases linearly with increasing concentration of HClO4 (70%) in acetonitrile (MeCN)at 298 K. In contrast to Sulfoxidation of thioanisoles by [(N4Py)FeIV(O)]2+, the observed second-order rate constant (ket) of electron transfer from one-electron reductants such as [FeII(Me2bpy)3]2+ (Me2bpy = 4,4-dimehtyl-2,2′-bipyridine) to [(N4Py)FeIV(O)]2+ increases with increasing concentration of HClO4, exhibiting second-order dependence on HClO4 concentration. This indicates that the proton-coupled electron transfer (PCET) involves two protons associated with electron transfer from [FeII(Me2bpy)3]2+ to [(N4Py)FeIV(O)]2+ to yield [FeIII(Me2bpy)3]3+ and [(N4Py)FeIII(OH2)]3+. The one-electron reduction potential (Ered)...
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metal ion effect on the switch of mechanism from direct oxygen transfer to metal ion coupled electron transfer in the Sulfoxidation of thioanisoles by a non heme iron iv oxo complex
Journal of the American Chemical Society, 2011Co-Authors: Jiyun Park, Wonwoo Nam, Yuma Morimoto, Yongmin Lee, Shunichi FukuzumiAbstract:The mechanism of Sulfoxidation of thioaniosoles by a non-heme iron(IV)−oxo complex is switched from direct oxygen transfer to metal ion-coupled electron transfer by the presence of Sc3+. The switch in the Sulfoxidation mechanism is dependent on the one-electron oxidation potentials of thioanisoles. The rate of Sulfoxidation is accelerated as much as 102-fold by the addition of Sc3+.
Jiyun Park - One of the best experts on this subject based on the ideXlab platform.
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unified view of oxidative c h bond cleavage and Sulfoxidation by a nonheme iron iv oxo complex via lewis acid promoted electron transfer
Inorganic Chemistry, 2014Co-Authors: Jiyun Park, Wonwoo Nam, Yuma Morimoto, Yongmin Lee, Shunichi FukuzumiAbstract:Oxidative C–H bond cleavage of toluene derivatives and Sulfoxidation of thioanisole derivatives by a nonheme iron(IV)–oxo complex, [(N4Py)FeIV(O)]2+ (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine), were remarkably enhanced by the presence of triflic acid (HOTf) and Sc(OTf)3 in acetonitrile at 298 K. All the logarithms of the observed second-order rate constants of both the oxidative C–H bond cleavage and Sulfoxidation reactions exhibit remarkably unified correlations with the driving forces of proton-coupled electron transfer (PCET) and metal ion-coupled electron transfer (MCET) in light of the Marcus theory of electron transfer when the differences in the formation constants of precursor complexes between PCET and MCET were taken into account, respectively. Thus, the mechanisms of both the oxidative C–H bond cleavage of toluene derivatives and Sulfoxidation of thioanisole derivatives by [(N4Py)FeIV(O)]2+ in the presence of HOTf and Sc(OTf)3 have been unified as the rate-determining electron...
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proton promoted oxygen atom transfer vs proton coupled electron transfer of a non heme iron iv oxo complex
Journal of the American Chemical Society, 2012Co-Authors: Jiyun Park, Wonwoo Nam, Yuma Morimoto, Yongmin Lee, Shunichi FukuzumiAbstract:Sulfoxidation of thioanisoles by a non-heme iron(IV)–oxo complex, [(N4Py)FeIV(O)]2+ (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine), was remarkably enhanced by perchloric acid (70% HClO4). The observed second-order rate constant (kobs) of Sulfoxidation of thioaniosoles by [(N4Py)FeIV(O)]2+ increases linearly with increasing concentration of HClO4 (70%) in acetonitrile (MeCN)at 298 K. In contrast to Sulfoxidation of thioanisoles by [(N4Py)FeIV(O)]2+, the observed second-order rate constant (ket) of electron transfer from one-electron reductants such as [FeII(Me2bpy)3]2+ (Me2bpy = 4,4-dimehtyl-2,2′-bipyridine) to [(N4Py)FeIV(O)]2+ increases with increasing concentration of HClO4, exhibiting second-order dependence on HClO4 concentration. This indicates that the proton-coupled electron transfer (PCET) involves two protons associated with electron transfer from [FeII(Me2bpy)3]2+ to [(N4Py)FeIV(O)]2+ to yield [FeIII(Me2bpy)3]3+ and [(N4Py)FeIII(OH2)]3+. The one-electron reduction potential (Ered)...
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metal ion effect on the switch of mechanism from direct oxygen transfer to metal ion coupled electron transfer in the Sulfoxidation of thioanisoles by a non heme iron iv oxo complex
Journal of the American Chemical Society, 2011Co-Authors: Jiyun Park, Wonwoo Nam, Yuma Morimoto, Yongmin Lee, Shunichi FukuzumiAbstract:The mechanism of Sulfoxidation of thioaniosoles by a non-heme iron(IV)−oxo complex is switched from direct oxygen transfer to metal ion-coupled electron transfer by the presence of Sc3+. The switch in the Sulfoxidation mechanism is dependent on the one-electron oxidation potentials of thioanisoles. The rate of Sulfoxidation is accelerated as much as 102-fold by the addition of Sc3+.
Wladyslawa A Daniel - One of the best experts on this subject based on the ideXlab platform.
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the influence of amitriptyline and carbamazepine on levomepromazine metabolism in human liver an in vitro study
Pharmacological Reports, 2014Co-Authors: Jacek Wojcikowski, Agnieszka Basinska, J Boksa, Wladyslawa A DanielAbstract:Abstract Background Joint administration of phenothiazine neuroleptics and an antidepressant or carbamazepine is applied in the therapy of many complex psychiatric disorders. The aim of the present study was to investigate possible effects of the tricyclic antidepressant drug amitriptyline and the anticonvulsant drug carbamazepine on the metabolism of the aliphatic-type phenothiazine neuroleptic levomepromazine in human liver. Methods The experiment was performed in vitro using human liver microsomes. The rates of levomepromazine 5-Sulfoxidation and N-demethylation (levomepromazine concentrations: 5, 10, 25 and 50 μM) were assessed in the absence and presence of amitriptyline or carbamazepine added in vitro (drug concentrations: 1, 2.5, 5, 10, 25 μM). Results A kinetic analysis of levomepromazine metabolism carried out in the absence or presence of carbamazepine showed that the anticonvulsant drug potently inhibited levomepromazine 5-Sulfoxidation ( K i = 7.6 μM, non-competitive inhibition), and moderately decreased the rate of levomepromazine N-demethylation ( K i = 15.4 μM, mixed inhibition) at therapeutic drug concentrations. On the other hand, amitriptyline weakly diminished the rate of levomepromazine 5-Sulfoxidation ( K i = 63 μM, mixed inhibition) and N-demethylation ( K i = 47.7 μM, mixed inhibition). Conclusion Regarding the central and peripheral effects of levomepromazine and some of its metabolites, the observed metabolic interaction between this neuroleptic and carbamazepine may be of pharmacological and clinical importance.
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the cytochrome p450 catalyzed metabolism of levomepromazine a phenothiazine neuroleptic with a wide spectrum of clinical application
Biochemical Pharmacology, 2014Co-Authors: Jacek Wojcikowski, Agnieszka Basinska, Wladyslawa A DanielAbstract:Abstract The aim of the present study was to identify cytochrome P450 isoenzymes (CYPs) involved in the 5-Sulfoxidation and N-demethylation of the aliphatic-type phenothiazine neuroleptic levomepromazine in human liver. Experiments were performed in vitro using cDNA-expressed human CYP isoforms (Supersomes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4), liver microsomes from different donors and CYP-selective inhibitors. The obtained results indicate that CYP3A4 is the main isoform responsible for levomepromazine 5-Sulfoxidation (72%) and N-demethylation (78%) at a therapeutic concentration of the drug (10 μM). CYP1A2 contributes to a lesser degree to levomepromazine 5-Sulfoxidation (20%). The role of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 in catalyzing the above-mentioned reactions is negligible (0.1–8%). Moreover, at a higher, toxicological concentration of the neuroleptic (100 μM), the relative contribution of CYP1A2 to levomepromazine metabolism visibly increases (from 20% to 28% for 5-sufoxidation, and from 8% to 32% for N-demethylation), while the role of CYP3A4 significantly decreases (from 72% to 59% for 5-Sulfoxidation, and from 78% to 47% for N-demethylation). The obtained results indicate that the catalysis of levomepromazine 5-Sulfoxidation and N-demethylation in humans shows a strict CYP3A4 preference, especially at a therapeutic drug concentration. Hence pharmacokinetic interactions involving levomepromazine and CYP3A4 substrates (e.g. tricyclic antidepressants, calcium channel antagonists, macrolide antibiotics, testosterone), inhibitors (e.g. ketoconazole, erythromycin, SSRIs) or inducers (e.g. rifampicin, carbamazepine) are likely to occur.
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main contribution of the cytochrome p450 isoenzyme 1a2 cyp1a2 to n demethylation and 5 Sulfoxidation of the phenothiazine neuroleptic chlorpromazine in human liver a comparison with other phenothiazines
Biochemical Pharmacology, 2010Co-Authors: Jacek Wojcikowski, J Boksa, Wladyslawa A DanielAbstract:Abstract The aim of the present study was to identify cytochrome P450 (CYP) isoenzymes involved in the 5-Sulfoxidation, mono-N-demethylation and di-N-demethylation of the aliphatic-type phenothiazine neuroleptic chlorpromazine in human liver. Experiments were performed in vitro using cDNA-expressed human CYP isoforms (Supersomes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4), liver microsomes from different donors and CYP-selective inhibitors. The obtained results indicate that CYP1A2 is the only CYP isoform that catalyzes the mono-N-demethylation and di-N-demethylation of chlorpromazine (100%) and is the main isoform responsible for chlorpromazine 5-Sulfoxidation (64%) at a therapeutic concentration of the drug (10 μM). CYP3A4 contributes to a lesser degree to chlorpromazine 5-Sulfoxidation (34%). The role of CYP2B6, CYP2C19 and CYP2D6 in catalyzing of the latter reaction is negligible (0.1–2%). Similar results were obtained at a higher, non-therapeutic concentration of the drug (100 μM); however, the contribution of CYP1A2 to chlorpromazine mono-N-demethylation was noticeably lower (75%), mostly in favour of CYP2C19 and CYP3A4 (about 12% each). The obtained results indicate that the catalysis of chlorpromazine N-demethylation and 5-Sulfoxidation in humans exhibits a stricter CYP1A2 preference compared to the previously tested phenothiazines (promazine, perazine, and thioridazine). Hence pharmacokinetic interactions involving chlorpromazine and CYP1A2 substrates and inhibitors are likely to occur. Considering strong dopaminergic D2, noradrenergic α1 and cholinergic M1 receptor blocking properties of chlorpromazine and some of its metabolites, as well as their serious side effects, the obtained results may be of pharmacological and clinical importance.
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characterization of human cytochrome p450 enzymes involved in the metabolism of the piperidine type phenothiazine neuroleptic thioridazine
Drug Metabolism and Disposition, 2006Co-Authors: Jacek Wojcikowski, Patrick Maurel, Wladyslawa A DanielAbstract:The aim of the present study was to identify human cytochrome P450 enzymes (P450s) involved in mono-2-, di-2-, and 5-Sulfoxidation, and N-demethylation of the piperidine-type phenothiazine neuroleptic thioridazine in the human liver. The experiments were performed in vitro using cDNA-expressed human P450s (Supersomes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4), liver microsomes from different donors, and P450-selective inhibitors. The results indicate that CYP1A2 and CYP3A4 are the main enzymes responsible for 5-Sulfoxidation and N-demethylation (34-52%), whereas CYP2D6 is the basic enzyme that catalyzes mono-2- and di-2-Sulfoxidation of thioridazine in human liver (49 and 64%, respectively). Besides CYP2D6, CYP3A4 contributes to a noticeable degree to thioridazine mono-2-Sulfoxidation (22%). Therefore, the sulforidazine/mesoridazine ratio may be an additional and more specific marker than the mesoridazine/thioridazine ratio for assessing the activity of CYP2D6. In contrast to promazine and perazine, CYP2C19 insignificantly contributes to the N-demethylation of thioridazine. Considering serious side-effects of thioridazine and its 5-sulfoxide (cardiotoxicity), as well as strong dopaminergic D2 and noradrenergic alpha1 receptor-blocking properties of mono-2- and di-2-sulfoxides, the obtained results are of pharmacological and clinical importance, in particular, in a combined therapy. Knowledge of the catalysis of thioridazine metabolism helps to choose optimum conditions (a proper coadministered drug and dosage) to avoid undesirable drug interactions.
