scholarly journals The Functions of Cytochrome P450 ω-hydroxylases and the Associated Eicosanoids in Inflammation-Related Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Kai-Di Ni ◽  
Jun-Yan Liu
Keyword(s):  
Fatty Acids ◽  
Cytochrome P450 ◽  
Leukotriene B4 ◽  
Hydroxyl Group ◽  
Epoxyeicosatrienoic Acids ◽  
Oxidation Reactions ◽  
Hydroxylated Metabolites ◽  
Associated Diseases ◽  
Exogenous Compounds

The cytochrome P450 (CYP) ω-hydroxylases are a subfamily of CYP enzymes. While CYPs are the main metabolic enzymes that mediate the oxidation reactions of many endogenous and exogenous compounds in the human body, CYP ω-hydroxylases mediate the metabolism of multiple fatty acids and their metabolites via the addition of a hydroxyl group to the ω- or (ω-1)-C atom of the substrates. The substrates of CYP ω-hydroxylases include but not limited to arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, epoxyeicosatrienoic acids, leukotrienes, and prostaglandins. The CYP ω-hydroxylases-mediated metabolites, such as 20-hyroxyleicosatrienoic acid (20-HETE), 19-HETE, 20-hydroxyl leukotriene B4 (20-OH-LTB4), and many ω-hydroxylated prostaglandins, have pleiotropic effects in inflammation and many inflammation-associated diseases. Here we reviewed the classification, tissue distribution of CYP ω-hydroxylases and the role of their hydroxylated metabolites in inflammation-associated diseases. We described up-regulation of CYP ω-hydroxylases may be a pathogenic mechanism of many inflammation-associated diseases and thus CYP ω-hydroxylases may be a therapeutic target for these diseases. CYP ω-hydroxylases-mediated eicosanods play important roles in inflammation as pro-inflammatory or anti-inflammatory mediators, participating in the process stimulated by cytokines and/or the process stimulating the production of multiple cytokines. However, most previous studies focused on 20-HETE,and further studies are needed for the function and mechanisms of other CYP ω-hydroxylases-mediated eicosanoids. We believe that our studies of CYP ω-hydroxylases and their associated eicosanoids will advance the translational and clinal use of CYP ω-hydroxylases inhibitors and activators in many diseases.

Cytochrome p450 2C (CYP2C) in ischemic heart injury and vascular dysfunctionThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigator's Forum.

2006 ◽  
Vol 84 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Manreet K. Chehal ◽  
David J. Granville
Keyword(s):  
Cytochrome P450 ◽  
Ischemic Heart ◽  
Epoxyeicosatrienoic Acids ◽  
Special Issue ◽  
Ischemia And Reperfusion Injury ◽  
Current Review ◽  
Cytochrome P450 2C ◽  
Heart Injury ◽  
Selection Of

The cytochrome p450 2C (CYP2C) monooxygenase family is a key player in the generation of epoxyeicosatrienoic acids. It has recently become apparent that CYP plays an important role in cardiovascular physiology and contributes to the pathogenesis of various cardiovascular diseases. In particular, several studies have demonstrated a role for these enzymes in cardiac ischemia and reperfusion injury. The current review summarizes the role of the CYP epoxygenase, CYP2C9, in ischemic heart disease and vascular homeostasis.

scholarly journals Exploring the Metabolism of Loxoprofen in Liver Microsomes: The Role of Cytochrome P450 and UDP-Glucuronosyltransferase in Its Biotransformation

Pharmaceutics ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 112 ◽  
Author(s):  
Riya Shrestha ◽  
Pil Cho ◽  
Sanjita Paudel ◽  
Aarajana Shrestha ◽  
Mi Kang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Active Metabolite ◽  
Experimental Studies ◽  
Liver Microsomes ◽  
Cytochrome P450s ◽  
Hydroxylated Metabolites ◽  
Udp Glucuronosyltransferase ◽  
Cyp Isoforms ◽  
Propionic Acid Derivative

Loxoprofen, a propionic acid derivative, non-steroidal anti-inflammatory drug (NSAID) is a prodrug that is reduced to its active metabolite, trans-alcohol form (Trans-OH) by carbonyl reductase enzyme in the liver. Previous studies demonstrated the hydroxylation and glucuronidation of loxoprofen. However, the specific enzymes catalyzing its metabolism have yet to be identified. In the present study, we investigated metabolic enzymes, such as cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), which are involved in the metabolism of loxoprofen. Eight microsomal metabolites of loxoprofen were identified, including two alcohol metabolites (M1 and M2), two mono-hydroxylated metabolites (M3 and M4), and four glucuronide conjugates (M5, M6, M7, and M8). Based on the results for the formation of metabolites when incubated in dexamethasone-induced microsomes, incubation with ketoconazole, and human recombinant cDNA-expressed cytochrome P450s, we identified CYP3A4 and CYP3A5 as the major CYP isoforms involved in the hydroxylation of loxoprofen (M3 and M4). Moreover, we identified that UGT2B7 is the major UGT isoform catalyzing the glucuronidation of loxoprofen and its alcoholic metabolites. Further experimental studies should be carried out to determine the potency and toxicity of these identified metabolites of loxoprofen, in order to fully understand of mechanism of loxoprofen toxicity.

scholarly journals Exploring the Role of Phenylalanine Residues in Modulating the Flexibility and Topography of the Active Site in the Peroxygenase Variant PaDa-I

2020 ◽  
Vol 21 (16) ◽  
pp. 5734
Author(s):  
Joaquin Ramirez-Ramirez ◽  
Javier Martin-Diaz ◽  
Nina Pastor ◽  
Miguel Alcalde ◽  
Marcela Ayala
Keyword(s):  
Hydrogen Peroxide ◽  
Cytochrome P450 ◽  
Active Site ◽  
Bulk Solution ◽  
Computational Studies ◽  
Organic Substrates ◽  
Oxidation Reactions ◽  
Heme Group ◽  
Wide Range

Unspecific peroxygenases (UPOs) are fungal heme-thiolate enzymes able to catalyze a wide range of oxidation reactions, such as peroxidase-like, catalase-like, haloperoxidase-like, and, most interestingly, cytochrome P450-like. One of the most outstanding properties of these enzymes is the ability to catalyze the oxidation a wide range of organic substrates (both aromatic and aliphatic) through cytochrome P450-like reactions (the so-called peroxygenase activity), which involves the insertion of an oxygen atom from hydrogen peroxide. To catalyze this reaction, the substrate must access a channel connecting the bulk solution to the heme group. The composition, shape, and flexibility of this channel surely modulate the catalytic ability of the enzymes in this family. In order to gain an understanding of the role of the residues comprising the channel, mutants derived from PaDa-I, a laboratory-evolved UPO variant from Agrocybe aegerita, were obtained. The two phenylalanine residues at the surface of the channel, which regulate the traffic towards the heme active site, were mutated by less bulky residues (alanine and leucine). The mutants were experimentally characterized, and computational studies (i.e., molecular dynamics (MD)) were performed. The results suggest that these residues are necessary to reduce the flexibility of the region and maintain the topography of the channel.

Atropselective Disposition of 2,2',3,4',6-Pentachlorobiphenyl (PCB 91) and Identification of Its Metabolites in Mice with Liver-specific Deletion of Cytochrome P450 Reductase

2019 ◽  
Author(s):  
Xianai Wu ◽  
Guangshu Zhai ◽  
Jerald L. Schnoor ◽  
Hans-Joachim Lehmler
Keyword(s):  
Cytochrome P450 ◽  
Hepatic Metabolism ◽  
Cytochrome P450 Reductase ◽  
Wild Type ◽  
Cytochrome P450 Enzymes ◽  
High Fat ◽  
Hydroxylated Metabolites ◽  
Chiral Polychlorinated Biphenyls ◽  
Specific Deletion

Cytochrome P450 enzymes oxidize chiral polychlorinated biphenyls (PCBs) to hydroxylated metabolites. Here we investigated the role of an impaired hepatic metabolism in the disposition of PCB 91 (CASRN 68194-05-8) in mice with a liver-specific deletion of the cpr gene (KO mice). KO mice and wild type (WT) mice were exposed to racemic PCB 91. Levels and enantiomeric fractions of PCB 91 and its metabolites were determined in tissues 3-days after PCB exposure. PCB 91 were higher in KO compared to WT mice. The liver of KO mice accumulated PCB 91 due to the high fat content in the liver of KO mice. 2,2',3,4',6-Pentachlorobiphenyl-5-ol was the major metabolite detected in all samples. PCB 91 and its metabolites displayed a genotype-dependent atropisomeric enrichment. These differences in atropselective disposition of PCB 91 and its metabolites are consistent with slower metabolism of PCB 91 in KO than WT mice and the accumulation of the parent PCB in the fatty liver of KO mice.<br>

scholarly journals The suppression of 5-lipoxygenation of arachidonic acid in human polymorphonuclear leucocytes by the 15-lipoxygenase product (15S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid: structure-activity relationship and mechanism of action

1996 ◽  
Vol 314 (3) ◽  
pp. 911-916 ◽  
Author(s):  
Karen PETRICH ◽  
Peter LUDWIG ◽  
Hartmut KÜHN ◽  
Tankred SCHEWE
Keyword(s):  
Fatty Acids ◽  
Arachidonic Acid ◽  
Leukotriene B4 ◽  
Eicosatetraenoic Acid ◽  
Ionophore A23187 ◽  
Polymorphonuclear Leucocytes ◽  
Lipoxygenase Inhibitor ◽  
Acid Structure ◽  
Selection Of

(15S)-Hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid (15-HETE) suppresses in ionophore-A23187-stimulated human polymorphonuclear leucocytes (PMN) the conversion of exogenous arachidonic acid into leukotriene B4 (LTB4) and (5S)-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoic acid (5-HETE). However, contrary to earlier suggestions, 15-HETE is not a genuine 5-lipoxygenase inhibitor under these conditions, but rather suppresses the 5-lipoxygenation of arachidonic acid by switching-over of substrate utilization, as judged from a sizeable formation of labelled (5S,15S)-dihydroxy-(6E,8Z,11Z,13E)-eicosatetraenoic acid (5,15-diHETE) from 15-[1-14C]HETE. Identical results were obtained with human recombinant 5-lipoxygenase. In PMN the formation of 5,15-diHETE is strongly stimulated by either hydroperoxypolyenoic fatty acids or arachidonic acid, suggesting a crucial role of the hydroperoxide tone of the cell. A comparison of a selection of hydroxypolyenoic fatty acids with respect to their capability of suppressing 5-lipoxygenation of arachidonic acid revealed that 15-monohydroxyeicosanoids throughout exhibit the highest inhibitory potencies, whereas the other HETEs, 5,15-diHETE as well as octadecanoids, are modest or poor inhibitors. The R and S enantiomers of 15-HETE do not differ from each other, excluding a receptor-like binding of the 15-hydroxy group.

Sign in / Sign up

Export Citation Format

Share Document