The human drug metabolizing cytochromes P450

1996 ◽  
Vol 24 (5) ◽  
pp. 461-473 ◽  
Author(s):  
Steven A. Wrighton ◽  
Mark VandenBranden ◽  
Barbara J. Ring
Keyword(s):  
Cytochromes P450

Molecular Basis of Iterative C–H Oxidation by TamI, a Multifunctional P450 Monooxygenase from the Tirandamycin Biosynthetic Pathway

2020 ◽  
Author(s):  
Sean A. Newmister ◽  
Kinshuk Raj Srivastava ◽  
Rosa V. Espinoza ◽  
Kersti Caddell Haatveit ◽  
Yogan Khatri ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Molecular Basis ◽  
Hydrophobic Interactions ◽  
Cytochromes P450 ◽  
Targeted Mutagenesis ◽  
P450 Monooxygenase ◽  
Bond Functionalization ◽  
Dynamics Simulations

Biocatalysis offers an expanding and powerful strategy to construct and diversify complex molecules by C-H bond functionalization. Due to their high selectivity, enzymes have become an essential tool for C-H bond functionalization and offer complementary reactivity to small-molecule catalysts. Hemoproteins, particularly cytochromes P450, have proven effective for selective oxidation of unactivated C-H bonds. Previously, we reported the in vitro characterization of an oxidative tailoring cascade in which TamI, a multifunctional P450 functions co-dependently with the TamL flavoprotein to catalyze regio- and stereoselective hydroxylations and epoxidation to yield tirandamycin A and tirandamycin B. TamI follows a defined order including 1) C10 hydroxylation, 2) C11/C12 epoxidation, and 3) C18 hydroxylation. Here we present a structural, biochemical, and computational investigation of TamI to understand the molecular basis of its substrate binding, diverse reactivity, and specific reaction sequence. The crystal structure of TamI in complex with tirandamycin C together with molecular dynamics simulations and targeted mutagenesis suggest that hydrophobic interactions with the polyene chain of its natural substrate are critical for molecular recognition. QM/MM calculations and molecular dynamics simulations of TamI with variant substrates provided detailed information on the molecular basis of sequential reactivity, and pattern of regio- and stereo-selectivity in catalyzing the three-step oxidative cascade.<br>

Structural Insights into Azole-based Inhibitors of Heme Oxygenase-1: Development of Selective Compounds for Therapeutic Applications

2019 ◽  
Vol 25 (42) ◽  
pp. 5803-5821 ◽  
Author(s):  
Mona N. Rahman ◽  
Dragic Vukomanovic ◽  
Jason Z. Vlahakis ◽  
Walter A. Szarek ◽  
Kanji Nakatsu ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Competitive Inhibition ◽  
Cytochromes P450 ◽  
Structural Similarity ◽  
Binding Pocket ◽  
Initial Study ◽  
Structural Basis ◽  
Heme Oxygenase 1 ◽  
Design Strategies ◽  
Inhibitor Binding

The development of isozyme-selective heme oxygenase (HO) inhibitors promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It is already known that HO has cytoprotective properties with a role in several disease states; thus, it is an enticing therapeutic target. Historically, the metalloporphyrins have been used as competitive HO inhibitors based on their structural similarity to the substrate, heme. However, heme’s important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), results in non-selectivity being an unfortunate side effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort over a decade ago to develop novel compounds as potent, selective inhibitors of HO. The result was the creation of the first generation of non-porphyrin based, non-competitive inhibitors with selectivity for HO, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the structures of several complexes of HO-1 with novel inhibitors have been elucidated and provided insightful information regarding the salient features required for inhibitor binding. This included the structural basis for non-competitive inhibition, flexibility and adaptability of the inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited in future drug-design strategies. Notably, HO-1 inhibitors are of particular interest for the treatment of hyperbilirubinemia and certain types of cancer. Key features based on this initial study have already been used by others to discover additional potential HO-1 inhibitors. Moreover, studies have begun to use selected compounds and determine their effects in some disease models.

Drug Interactions with Angiotensin Receptor Blockers: Role of Human Cytochromes P450

2016 ◽  
Vol 17 (7) ◽  
pp. 681-691 ◽  
Author(s):  
Ruirui Yang ◽  
Zhiqiang Luo ◽  
Yang Liu ◽  
Mohan Sun ◽  
Ling Zheng ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Cytochromes P450 ◽  
Angiotensin Receptor Blockers ◽  
Angiotensin Receptor ◽  
Receptor Blockers

Peroxidases from Tulip Bulbs (Tulipa fosteriana, L.) Oxidize Xenobiotics NNitrosodimethylamine and N-Nitroso-N-methylaniline in vitro

1997 ◽  
Vol 62 (11) ◽  
pp. 1804-1814 ◽  
Author(s):  
Marie Stiborová ◽  
Hana Hansíková
Keyword(s):  
Cytochromes P450 ◽  
Kinetic Studies ◽  
The Other ◽  
Maximal Velocity ◽  
Michaelis Constant ◽  
Other Hand ◽  
Plant Peroxidases ◽  
Tulip Bulbs

Tulip bulbs (Tulipa fosteriana, L.) contain peroxidases catalyzing the oxidation of the xenobiotics N-nitrosodimethylamine (NDMA) and N-nitroso-N-methylaniline (NMA). Three anionic (A1, A2, A3) and four cationic (B, C, D, E) peroxidases were purified from this tissue, partially characterized and used for kinetic studies. Demethylation of NDMA and NMA producing formaldehyde is catalyzed by one anionic (A1) and three cationic (C, D, E) peroxidases. The oxidation of NDMA by tulip peroxidases exhibits the Michaelis-Menten kinetics. The apparent Michaelis constant and the maximal velocity values for this substrate were determined. On the other hand, non-Michaelian kinetics for the NMA oxidation were observed with tulip peroxidases. The most abundant cationic peroxidase (peroxidase C) was used for detailed enzymatic studies. In addition to formation of formaldehyde, methylaniline, aniline, 4-aminophenol and phenol were found to be metabolites formed from NMA. Phenol was formed presumably by N-demethylation via a benzenediazonium ion, while methylaniline, aniline and 4-aminophenol were products of denitrosation of the substrate. The efficiencies of plant peroxidases to oxidize NDMA and NMA in vitro are compared with those of cytochromes P450 and discussed.

Chicken Egg Yolk as an Excellent Source of Highly Specific Antibodies Against Cytochromes P450

2004 ◽  
Vol 69 (3) ◽  
pp. 659-673 ◽  
Author(s):  
Petr Hodek ◽  
Tomáš Koblas ◽  
Helena Rýdlová ◽  
Božena Kubíčková ◽  
Miroslav Šulc ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cytochromes P450 ◽  
Egg Yolk ◽  
Good Alternative ◽  
Invasive Technique ◽  
Cytochrome P450 1A1 ◽  
Orconectes Limosus ◽  
Chicken Egg ◽  
Cytochrome P450 2B4 ◽  
Human Livers

Using chicken antibodies IgY (purified from egg yolks) against mammalian cytochromes P450 and by means of cytochrome P450 marker substrates, we found for the first time the presence of hepatopancreatic cytochrome P450 in crayfishOrconectes limosus(an inducible cytochrome P450 2B-like enzyme) and we were able to detect and quantify cytochrome P450 1A1 in microsomes of human livers. Expression levels of cytochrome P450 1A1 in human livers constituted less than 0.6% of the total hepatic cytochrome P450 complement. The results obtained in our study are clear examples that chicken IgY are suitable for cytochrome P450 detection and quantification. Due to the evolutionary distance, chicken IgY reacts with more epitopes on a mammalian antigen, which gives an amplification of the signal. Moreover, this approach offers many advantages over common mammalian antibody production since chicken egg is an abundant source of antibodies (about 100 mg IgY/yolk) and the egg collection is a non-invasive technique. In the case of antibodies against cytochrome P450 2B4, we documented fast and steady production of highly specific immunoglobulins. Thus, chicken antibodies should be considered as a good alternative to and/or superior substitute for conventional polyclonal antibody produced in mammals.

Hepatocellular carcinoma: Gene expression profiling and regulation of xenobiotic-metabolizing cytochromes P450

2020 ◽  
Vol 177 ◽  
pp. 113912 ◽  
Author(s):  
Jana Nekvindova ◽  
Alena Mrkvicova ◽  
Veronika Zubanova ◽  
Alena Hyrslova Vaculova ◽  
Pavel Anzenbacher ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cytochromes P450

Five genetic polymorphisms of cytochrome P450 enzymes in the Czech non-Roma and Czech Roma population samples

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Lucie Dlouhá ◽  
Věra Adámková ◽  
Lenka Šedová ◽  
Věra Olišarová ◽  
Jaroslav A. Hubáček ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Genetic Polymorphisms ◽  
Metabolic Pathways ◽  
Cytochromes P450 ◽  
Taqman Assay ◽  
Cytochrome P450 Enzymes ◽  
Roma Population ◽  
Czech Population ◽  
Genotype Frequencies ◽  
Pcr Rflp

AbstractObjectivesCytochromes P450 play a role in human drugs metabolic pathways and their genes are among the most variable in humans. The aim of this study was to analyze genotype frequencies of five common polymorphisms of cytochromes P450 in Roma/Gypsy and Czech (non-Roma) population samples with Czech origin.MethodsRoma/Gypsy (n=302) and Czech subjects (n=298) were genotyped for CYP1A2 (rs762551), CYP2A6 (rs4105144), CYP2B6 (rs3745274) and CYP2D6 (rs3892097; rs1065852) polymorphisms using PCR-RFLP or Taqman assay.ResultsWe found significant allelic/genotype differences between ethnics in three genes. For rs3745274 polymorphism, there was increased frequency of T allele carriers in Roma in comparison with Czech population (53.1 vs. 43.7%; p=0.02). For rs4105144 (CYP2A6) there was higher frequency of T allele carriers in Roma in comparison with Czech population (68.7 vs. 49.8%; p<0.0001). For rs3892097 (CYP2D6) there was more carriers of the A allele between Roma in comparison with Czech population (39.2 vs. 38.2%; p=0.048). Genotype/allelic frequencies of CYP2D6 (rs1065852) and CYP1A2 (rs762551) variants did not significantly differ between the ethnics.ConclusionsThere were significant differences in allelic/genotype frequencies of some, but not all cytochromes P450 polymorphisms between the Czech Roma/Gypsies and Czech non-Roma subjects.

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