Cytochrome P450 2J2 (EC 1.14.14.-) (Albendazole monooxygenase (hydroxylating)) (EC 1.14.14.74) (Albendazole monooxygenase (sulfoxide-forming)) (EC 1.14.14.73) (Arachidonic acid epoxygenase) (CYPIIJ2) (Hydroperoxy icosatetraenoate isomerase) (EC 5.4.4.7)

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The effects of endothelium-specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model.

Glaucoma is a leading cause of irreversible blindness worldwide. Vascular factors play a substantial role in the pathogenesis of glaucoma. Expressed in the vascular endothelium, cytochrome P450 (CYP) 2J2 is one of the CYP epoxygenases that metabolize arachidonic acid to produce epoxyeicosatrienoic acids and exert pleiotropic protective effects on the vasculature. In the present study, we investigated whether endothelium-specific overexpression of CYP2J2 (tie2-CYP2J2-Tr) protects against retinal ganglion cell (RGC) loss induced by glaucoma and in what way retinal vessels are involved in this process. We used a glaucoma model of retinal ischemia-reperfusion (I/R) injury in rats and found that endothelium-specific overexpression of CYP2J2 attenuated RGC loss induced by retinal I/R. Moreover, retinal I/R triggered retinal vascular senescence, indicated by up-regulated senescence-related proteins p53, p16, and β-galactosidase activity. The senescent endothelial cells resulted in pericyte loss and increased endothelial secretion of matrix metallopeptidase 9, which further contributed to RGC loss. CYP2J2 overexpression alleviated vascular senescence, pericyte loss, and matrix metallopeptidase 9 secretion. CYP2J2 suppressed endothelial senescence by down-regulating senescence-associated proteins p53 and p16. These 2 proteins were positively regulated by microRNA-128-3p, which was inhibited by CYP2J2. These results suggest that CYP2J2 protects against endothelial senescence and RGC loss in glaucoma, a discovery that may lead to the development of a potential treatment strategy for glaucoma.-Huang, J., Zhao, Q., Li, M., Duan, Q., Zhao, Y., Zhang, H. The effects of endothelium-specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model.

MeSH Terms

  • Animals
  • Apoptosis
  • Cellular Senescence
  • Cytochrome P-450 Enzyme System
  • Disease Models, Animal
  • Down-Regulation
  • Endothelial Cells
  • Endothelium, Vascular
  • Glaucoma
  • Metalloendopeptidases
  • MicroRNAs
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury
  • Retinal Ganglion Cells
  • Tumor Suppressor Protein p53
  • Up-Regulation

Keywords

  • MMPs
  • microRNAs
  • retinal vasculature
  • senescence


Regional vulnerability to lipoxidative damage and inflammation in normal human brain aging.

Oxidative damage and inflammation coexist in healthy human brain aging. The present study analyzes levels of protein adduction by lipid peroxidation (LP) end-products neuroketal (NKT) and malondialdehyde (MDA), as markers of protein oxidative damage, cycloxygenase-2 (COX-2) levels, as a marker of inflammation, and cytochrome P450 2J2 (CYP2J2), responsible of generation of neuroprotective products, in twelve brain regions in normal middle-aged individuals (MA) and old-aged (OA) individuals. In addition, levels of these markers were evaluated as a function of age as a continuous variable and correction for multiple comparisons. Selection of regions was based on their different vulnerability to prevalent neurodegenerative diseases in aging. Our findings show region-dependent LP end-products, COX-2 and CYP2J2 changes in the aging human brain. However, no clear relationship can be established between NKT, MDA, COX-2 and CYP2J2 levels, and regional vulnerability to neurodegeneration in old age.

MeSH Terms

  • Adult
  • Aged
  • Aging
  • Blotting, Western
  • Brain
  • Cytochrome P-450 Enzyme System
  • Female
  • Humans
  • Inflammation
  • Lipid Peroxidation
  • Male
  • Malondialdehyde
  • Middle Aged
  • Oxidative Stress

Keywords

  • Brain aging
  • COX-2
  • CYP2J2
  • MDA
  • NKT
  • Neuroinflammation
  • Neuroprotection
  • Oxidative stress
  • Regional vulnerability


Endothelium-specific CYP2J2 overexpression attenuates age-related insulin resistance.

Ample evidences demonstrate that cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) exert diverse biological activities, which include potent vasodilatory, anti-inflammatory, and cardiovascular protective effects. In this study, we investigated the effects of endothelium-specific CYP2J2 overexpression on age-related insulin resistance and metabolic dysfunction. Endothelium-specific targeting of the human CYP epoxygenase, CYP2J2, transgenic mice (Tie2-CYP2J2-Tr mice) was utilized. The effects of endothelium-specific CYP2J2 overexpression on aging-associated obesity, inflammation, and peripheral insulin resistance were evaluated by assessing metabolic parameters in young (3 months old) and aged (16 months old) adult male Tie2-CYP2J2-Tr mice. Decreased insulin sensitivity and attenuated insulin signaling in aged skeletal muscle, adipose tissue, and liver were observed in aged adult male mice, and moreover, these effects were partly inhibited in 16-month-old CYP2J2-Tr mice. In addition, CYP2J2 overexpression-mediated insulin sensitization in aged mice was associated with the amelioration of inflammatory state. Notably, the aging-associated increases in fat mass and adipocyte size were only observed in 16-month-old wild-type mice, and CYP2J2 overexpression markedly prevented the increase in fat mass and adipocyte size in aged Tie2-CYP2J2-Tr mice, which was associated with increased energy expenditure and decreased lipogenic genes expression. Furthermore, these antiaging phenotypes of Tie2-CYP2J2-Tr mice were also associated with increased muscle blood flow, enhanced active-phase locomotor activity, and improved mitochondrial dysfunction in skeletal muscle. Collectively, our findings indicated that endothelium-specific CYP2J2 overexpression alleviated age-related insulin resistance and metabolic dysfunction, which highlighted CYP epoxygenase-EET system as a potential target for combating aging-related metabolic disorders.

MeSH Terms

  • Adipose Tissue
  • Age Factors
  • Animals
  • Cytochrome P-450 Enzyme System
  • Eicosanoids
  • Humans
  • Inflammation
  • Insulin
  • Insulin Resistance
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Skeletal

Keywords

  • CYP2J2
  • adipose tissue
  • aging
  • inflammation
  • insulin resistance


In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies.

Apixaban is an oral, direct, and highly selective factor Xa inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. The metabolic drug-drug interaction potential of apixaban was evaluated in vitro. The compound did not show cytochrome P450 inhibition (IC(50) values >20 microM) in incubations of human liver microsomes with the probe substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Apixaban did not show any effect at concentrations up to 20 muM on enzyme activities or mRNA levels of selected P450 enzymes (CYP1A2, 2B6, and 3A4/5) that are sensitive to induction in incubations with primary human hepatocytes. Apixaban showed a slow metabolic turnover in incubations of human liver microsomes with formation of O-demethylation (M2) and hydroxylation products (M4 and M7) as prominent in vitro metabolites. Experiments with human cDNA-expressed P450 enzymes and P450 chemical inhibitors and correlation with P450 activities in individual human liver microsomes demonstrated that the oxidative metabolism of apixaban for formation of all metabolites was predominantly catalyzed by CYP3A4/5 with a minor contribution of CYP1A2 and CYP2J2 for formation of M2. The contribution of CYP2C8, 2C9, and 2C19 to metabolism of apixaban was less significant. In addition, a human absorption, distribution, metabolism, and excretion study showed that more than half of the dose was excreted as unchanged parent (f(m CYP) <0.5), thus significantly reducing the overall metabolic drug-drug interaction potential of apixaban. Together with a low clinical efficacious concentration and multiple clearance pathways, these results demonstrate that the metabolic drug-drug interaction potential between apixaban and coadministered drugs is low.

MeSH Terms

  • Aging
  • Anticoagulants
  • Cells, Cultured
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System
  • Drug Evaluation, Preclinical
  • Drug Interactions
  • Factor Xa Inhibitors
  • Hepatocytes
  • Humans
  • Hydroxylation
  • Isoenzymes
  • Kinetics
  • Metabolic Detoxication, Phase I
  • Microsomes
  • Organ Specificity
  • Pyrazoles
  • Pyridones
  • RNA, Messenger
  • Recombinant Proteins