21‐Aminosteroids prevent the down‐regulation of hepatic cytochrome P450 induced by hypoxia and inflammation in conscious rabbits

Galal, A.; Souich, Patrick du

doi:10.1038/sj.bjp.0702796

Cited by 11 publications

(9 citation statements)

References 52 publications

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“…In experimental animals and in humans, hypoxia alone or hypoxia and inflammation modulated CYP450 enzymes causing both a down-regulation of total hepatic CYP450 content and expression of some CYP450 isoenzymes as well as an up-regulation of other isoenzymes and their mRNA through the release of numerous cytokines such as IL-1␤, IL-2, IL-4, IL-5, TNF-␣, and IFN-␥, [151][152][153][154] and erythropoietin, 155,156 which can induce changes in the expression of CYP450 genes. 157,158 Hypoxia triggered also the expression and release of various inflammatory mediator receptor antagonists in a variety of cell types, eg, in mitogen-activated mononuclear cells, hypoxia enhanced IL-1 receptor antagonist (IL-1 Ra) mRNA expression and concomitantly increased, albeit to a lesser extent, both IL-1␣ and IL-1␤ mRNA expression and release in the surrounding environment.…”

Section: Abnormalities In the Central Nervous Systemmentioning

confidence: 99%

Possible Pathomechanisms of Sudden Infant Death Syndrome

Prandota¹

2004

American Journal of Therapeutics

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Chronic hypoxia, viral infections/bacterial toxins, inflammation states, biochemical disorders, and genetic abnormalities are the most likely trigger of sudden infant death syndrome (SIDS). Autopsy studies have shown increased pulmonary density of macrophages and markedly more eosinophils in the lungs accompanied by increased T and B lymphocytes. The elevated levels of immunoglobulins, about 20% more muscle in the pulmonary arteries, increased airway smooth muscle cells, and increased fetal hemoglobin and erythropoietin are evidence of chronic hypoxia before death. Other abnormal findings included mucosal immune stimulation of the tracheal wall, duodenal mucosa, and palatine tonsils, and circulating interferon. Low normal or higher blood levels of cortisol often with petechiae on intrathoracic organs, depleted maternal IgG antibodies to endotoxin core (EndoCAb) and early IgM EndoCAb triggered, partial deletions of the C4 gene, and frequent IL-10-592*A polymorphism in SIDS victims as well as possible hypoxia-induced decreased production of antiinflammatory, antiimmune, and antifibrotic cytokine IL-10, may be responsible for the excessive reactions to otherwise harmless infections. In SIDS infants, during chronic hypoxia and times of infection/inflammation, several proinflammatory cytokines are released in large quantities, sometimes also representing a potential source of tissue damage if their production is not sufficiently well controlled, eg, by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). These proinflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting metabolism of several endogenous lipophilic substances, such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances. In SIDS victims, chronic hypoxia, TNF-alpha and other inflammatory cytokines, and arachidonic acid (AA) as well as n-3 polyunsaturated fatty acids (FA), stimulated and/or augmented superoxide generation by polymorphonuclear leukocytes, which contributed to tissue damage. Chronic hypoxia, increased amounts of nonheme iron in the liver and adrenals of these infants, enhanced activity of CYP2C9 regarded as the functional source of reactive oxygen species (ROS) in some endothelial cells, and nicotine accumulation in tissues also intensified production of ROS. These increased quantities of proinflammatory cytokines, ROS, AA, and nitric oxide (NO) also resulted in suppression of many CYP450 and other enzymes, eg, phosphoenolpyruvate carboxykinase (PEPCK), an enzyme important in the metabolism of FA during gluconeogenesis and glyceroneogenesis. PEPCK deficit found in SIDS infants (caused also by vitamin A deficiency) and eventually enhanced by PACAP lipolysis of adipocyte triglycerides resulted in an increased FA level in blood because of their impaired reesterification to triacylglycerol in adipocytes. In ...

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Section: Abnormalities In the Central Nervous Systemmentioning

confidence: 99%

Possible Pathomechanisms of Sudden Infant Death Syndrome

Prandota¹

2004

American Journal of Therapeutics

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“…In experimental septicemia, modification of P450 isoforms at peak nitric oxide (NO) generation at 8–12 h upsets a quantitative balance. ROS induced by hypoxia or inflammatory reaction has been implicated in the signaling pathway leading to P450 downregulation in vivo 11 . However, the cascade of events leading to the downregulation of P450 in endotoxemia remains poorly defined.…”

Section: Introductionmentioning

confidence: 99%

“…ROS induced by hypoxia or inflammatory reaction has been implicated in the signaling pathway leading to P450 downregulation in vivo. 11 However, the cascade of events leading to the downregulation of P450 in endotoxemia remains poorly defined. It is not known whether overexpression of CYP3A (major P450 isoform) will induce liver injury in endotoxemia.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of CYP3A aggravates endotoxin‐induced liver injury in hypophysectomized female rats

Takemura¹,

Minamiyama

Toyokuni

et al. 2007

Hepatology Research

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“…Moreover, in vivo, the antioxidant U74389G prevents the decrease in CYP1A2 activity produced by the turpentine-induced inflammatory reaction (Galal and Souich, 1999).…”

Section: Kourylko Et Almentioning

confidence: 99%

Modulation of Cyp1a2 and Cyp3a6 Catalytic Activities by Serum From Rabbits With a Turpentine-Induced Inflammatory Reaction and Interleukin 6

Kourylko

Fradette²,

Arcand³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Inflammatory reactions reduce the activity of cytochrome P450 isoforms. The aim of the study was to determine the mechanisms underlying the decrease in CYP1A2 and CYP3A6 catalytic activities produced by serum from rabbits with a turpentine-induced inflammatory reaction (S TIIR ) and interleukin 6 (IL-6). S TIIR and IL-6 were incubated with cultured primary hepatocytes from control rabbits (H CONT ), and from rabbits with a turpentine-induced inflammatory reaction (H TIIR ) in the absence or presence of pyrrolidine dithiocarbamate (PDTC), an antioxidant and inhibitor of nuclear factor B transcription; 2-amino-3-methoxyflavone (PD98059), an inhibitor of extracellular signal-related kinase (Erk1/2); 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), an inhibitor of p38MAPK; N -nitro-L-arginine methyl ester, an inhibitor of nitric-oxide synthase 2 (NOS2); the combination of PDTC, PD98059, and SB203580; and genistein, an inhibitor of Janus-associated protein tyrosine kinase (JAK). After 4 and 24 h of incubation of H CONT with S TIIR and IL-6, CYP1A2 activity was reduced without changes in expression; the reduction in activity was partially prevented by the inhibition of JAK, Erk1/2, and NOS2. In H CONT , S TIIR and IL-6 did not affect CYP3A6 activity; however, PDTC reduced CYP3A6 activity by 40 and 80% after 4 and 24 h of incubation. In H TIIR , S TIIR and IL-6 reduced both CYP1A2 and CYP3A6 activities; this decrease is partially prevented by inhibitors of protein tyrosine kinases, Erk1/2, and NOS2. In H TIIR , SB203580 increased CYP3A6 activity in a dose-dependent manner without changes in protein expression. These results show that the signal transduction pathways mediating the decrease in CYP1A2 and 3A6 activity, produced by S TIIR and IL-6, involve JAK, Erk1/2, and NOS2.There is considerable evidence that in humans an inflammatory reaction can diminish the activity of the cytochrome P450 (P450) superfamily . The first documented observation reported that an upper respiratory viral infection in asthmatic children increased theophylline plasma concentrations and half-life (Chang et al., 1978). Actually, numerous reports have documented that influenza infections reduce the rate of biotransformation of theophylline and other drugs (Cheng and Morgan, 2001;Renton, 2001). Moreover, bacterial respiratory infections, as well as chronic obstructive lung disease, reduce the ability of the organism to clear xenobiotics (Sonne et al., 1985). Other causes of inflammation, such as elective surgery, reduce the activity of CYP3A4 (Haas et al., 2003). Using animal models, it has been shown that various models of inflammation, such as the injection of lipopolysaccharide (LPS), turpentine, and carrageenan depress the activity of the P450 (Cheng and Morgan, 2001;Renton, 2001).Already in 1978, the decrease in theophylline clearance was attributed to the down-regulation of P450 isoforms (Renton, 1978). Since then, many reports have confirmed that an inflammatory reaction triggers the release of...

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21‐Aminosteroids prevent the down‐regulation of hepatic cytochrome P450 induced by hypoxia and inflammation in conscious rabbits

Cited by 11 publications

References 52 publications

Possible Pathomechanisms of Sudden Infant Death Syndrome

Possible Pathomechanisms of Sudden Infant Death Syndrome

Overexpression of CYP3A aggravates endotoxin‐induced liver injury in hypophysectomized female rats

Modulation of Cyp1a2 and Cyp3a6 Catalytic Activities by Serum From Rabbits With a Turpentine-Induced Inflammatory Reaction and Interleukin 6

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