Effect of hypoxia alone or combined with inflammation and 3‐methylcholanthrene on hepatic cytochrome P450 in conscious rabbits

Kurdi, J; Maurice, Hélène; El‐Kadi, Ayman O.S.; Ong, Huy; Dalkara, Sevim; Bélanger, Patrick; Souich, Patrick du

doi:10.1038/sj.bjp.0702795

Cited by 30 publications

(25 citation statements)

References 59 publications

(71 reference statements)

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“…In particular, obese individuals with systemic hypoxemia (because of sleep-related breathing disorders including obstructive sleep apnea) may experience repeated bouts of hepatic hypoxia, hepatocyte necrosis, and ultimately develop NASH. Several pieces of evidence support the possibility that hypoxemia may play a role in pathogenesis of NASH: First, sleep disturbances and nocturnal hypoxemia are common in patients with NASH (Table 2); second, hypoxemia has been shown to alter the activity of different CYPs 27,28 ; third, sleep apnea and hypoxemia have been associated with lipid peroxidation and oxidative stress 29 ; and, fourth, in the dietary model of animal NASH 6 as well as the human study by Weltman et al, 8 CYP2E1 activity was most prominent in zone III, the least oxygenated area of the acinus. The significant association noted in this study between hepatic CYP2E1 activity and nocturnal hypoxemia is interesting.…”

Section: Discussionmentioning

confidence: 99%

Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis

et al. 2003

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Cytochrome P450 2E1 (CYP2E1) plays an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH) in animal models, but its role in the pathogenesis of human NASH is unclear. Therefore, we measured hepatic CYP2E1 activity and its correlates in a cohort of nondiabetic patients with NASH (NDN) and controls to explore its role in the pathogenesis of human NASH. Hepatic CYP2E1 activity was assessed using the oral clearance (CL PO ) of chlorzoxazone (CHZ) in 20 NDN and 17 age, gender, and body mass index (BMI)-matched controls. The relationship between hepatic CYP2E1 activity and demographic and anthropometric variables; fasting levels of insulin, glucose, lipids, and ␤-OH butyrate; insulin resistance; and nocturnal hypoxemia was assessed. Furthermore, expression of CYP2E1 in the peripheral lymphocytes was assessed using reverse transcription-polymerase chain reaction (RT-PCR). The CL PO of CHZ was significantly (P ‫؍‬ .03) greater in NDN (41 ؎ 12 L/h) compared with controls (33 ؎ 16 L/h). Lymphocyte CYP2E1 messenger RNA was significantly higher in NDN compared with controls (11.5 ؋ 10 3 ؎ 10 ؋ 10 3 vs. 2.6 ؋ 10 3 ؎ 1.2 ؋ 10 3 molecules/ g total RNA, respectively, P < .001). On univariate analysis, BMI, respiratory quotient, high-density lipoprotein, triglycerides, insulin, insulin resistance, hypoxemia, and ␤-OH butyrate significantly correlated with hepatic CYP2E1 activity. However, on stepwise regression analysis, only nocturnal hypoxemia (r ‫؍‬ 0.50, P ‫؍‬ .009) and ␤-OH butyrate (r ‫؍‬ 0.37, P ‫؍‬ .04) were independent predictors of hepatic CYP2E1 activity. In conclusion, hepatic CYP2E1 activity and lymphocyte CYP2E1 expression are enhanced in NDN. The significant correlations noted between CYP2E1 and hypoxemia and ␤-OH butyrate suggest that these factors play a role in increased CYP2E1 activity that is seen in patients with NASH. (HEPATOLOGY 2003;37:544-550.)

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Section: Discussionmentioning

confidence: 99%

Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis

et al. 2003

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“…It was found that the serum of rabbits with acute inflammatory reaction down-regulate various CYP enzymes noncompetitively through several mediators [120]. In addition, it has been reported that acute moderate hypoxia and inflammation individually inhibited CYP; nevertheless, the combination of hypoxia and the inflammatory reaction restores CYP activity [110]. It was postulated that hypoxia can inhibit T-cell function which is necessary for the CYP down-regulation during inflammatory reaction [110].…”

Section: Pro-inflammatory Cytokinesmentioning

confidence: 99%

Modulation of Cardiac and Hepatic Cytochrome P450 Enzymes During Heart Failure

Zordoky¹,

El‐Kadi

2008

CDM

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Heart failure is a very serious cardiovascular disease that affects more than five million people in North America. The role of cytochrome P450 (CYP) in cardiovascular health and disease is well established. Many CYP enzymes have been identified in the heart and their levels have been reported to be altered during cardiac hypertrophy and heart failure. There is a great deal of discrepancy between various reports on CYP alterations during heart failure, likely due to differences in disease severity, species in question and other underlying conditions. In general, however, cardiac CYP1B and CYP2A, CYP2B, CYP2E, CYP2J, CYP4A and CYP11 mRNA levels and related enzyme activities are usually increased. Moreover, there is a strong correlation between CYP-mediated endogenous metabolites and the pathogenesis of cardiac hypertrophy and heart failure. Some of these metabolites confer cardioprotective effect such as estradiol, dehydroepiandrosterone, epoxyeicosatrienoic acids, and prostaglandin I(2); whereas, other metabolites may be harmful to the heart such as androgens, aldosterone, hydroxyeicosatetraenoic acids, and thromboxane A(2). On the other hand, heart failure plays an important role in the down-regulation of hepatic CYP involved in drug metabolism through several mechanisms which include hepatocellular damage, hypoxia, elevated levels of pro-inflammatory cytokines, and increased production of heme oxygenase-1. Therefore, more research is needed to elucidate the mechanisms by which CYP affect the development and/or progression of heart failure and also the mechanism by which heart failure alters cardiac and hepatic CYP enzymes.

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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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Effect of hypoxia alone or combined with inflammation and 3‐methylcholanthrene on hepatic cytochrome P450 in conscious rabbits

Cited by 30 publications

References 59 publications

Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis

Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis

Modulation of Cardiac and Hepatic Cytochrome P450 Enzymes During Heart Failure

Possible Pathomechanisms of Sudden Infant Death Syndrome

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