Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

Oesch, Franz; Fabian, Eric; Landsiedel, Robert

doi:10.1007/s00204-019-02602-7

Cited by 47 publications

(29 citation statements)

References 416 publications

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“…Two types of primary cells were used: pig alveolar macrophages (PAMs) and pig hepatocytes (PHCs). PAMs have strong immune significance, whereas PHCs have strong metabolizing functions, although both types of cells share these functions (43)(44)(45)(46). As shown in Figures S3A, B, primary cells with high purity were isolated and cultured.…”

Section: Inverse Regulation Of Inflammation By 2-ag and Plementioning

confidence: 99%

Pig Liver Esterases Hydrolyze Endocannabinoids and Promote Inflammatory Response

et al. 2021

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Endocannabinoids are endogenous ligands of cannabinoid receptors and activation of these receptors has strong physiological and pathological significance. Structurally, endocannabinoids are esters (e.g., 2-arachidonoylglycerol, 2-AG) or amides (e.g., N-arachidonoylethanolamine, AEA). Hydrolysis of these compounds yields arachidonic acid (AA), a major precursor of proinflammatory mediators such as prostaglandin E2. Carboxylesterases are known to hydrolyze esters and amides with high efficiency. CES1, a human carboxylesterase, has been shown to hydrolyze 2-AG, and shares a high sequence identity with pig carboxylesterases: PLE1 and PLE6 (pig liver esterase). The present study was designed to test the hypothesis that PLE1 and PLE6 hydrolyze endocannabinoids and promote inflammatory response. Consistent with the hypothesis, purified PLE1 and PLE6 efficaciously hydrolyzed 2-AG and AEA. PLE6 was 40-fold and 3-fold as active as PLE1 towards 2-AG and AEA, respectively. In addition, both PLE1 and PLE6 were highly sensitive to bis(4-nitrophenyl) phosphate (BNPP), an aryl phosphodiester known to predominately inhibit carboxylesterases. Based on the study with BNPP, PLEs contributed to the hydrolysis of 2-AG by 53.4 to 88.4% among various organs and cells. Critically, exogenous addition or transfection of PLE6 increased the expression and secretion of proinflammatory cytokines in response to the immunostimulant lipopolysaccharide (LPS). This increase was recapitulated in cocultured alveolar macrophages and PLE6 transfected cells in transwells. Finally, BNPP reduced inflammation trigged by LPS accompanied by reduced formation of AA and proinflammatory mediators. These findings define an innovative connection: PLE-endocannabinoid-inflammation. This mechanistic connection signifies critical roles of carboxylesterases in pathophysiological processes related to the metabolism of endocannabinoids.

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Section: Inverse Regulation Of Inflammation By 2-ag and Plementioning

confidence: 99%

Pig Liver Esterases Hydrolyze Endocannabinoids and Promote Inflammatory Response

et al. 2021

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“…Major KEGG signaling pathways observed with significant changes included vascular smooth muscle contraction, osteoclast differentiation, hypertrophic cardiomyopathy, dilated cardiomyopathy pathways, and metabolism of xenobiotics by cytochrome P450 (CYP450). In those pathways, major pathways were associated with cardiovascular disease, osteoclast differentiation and CYP450 enzyme; Plenty studies showed that the expression of CYP450 was related to the metabolism of various exogenous compounds has an impact on the lung damage caused by PM 2.5 (Saint-Georges et al, 2008;Abbas et al, 2009;Oesch et al, 2019), we chose to further explore the "Metabolism of xenobiotics by cytochrome P450" pathway. This pathway enrichment contains 18 genes and their p-value was 0.01.…”

Section: Results Effects Of Nuclear Factor Erythroid 2-related Factor 2 On Pulmonary Function and Pathology In Pm 25 -Exposed Micementioning

confidence: 99%

“…CYP450 participates in the metabolism of exogenous substances, including drugs and environmental compounds. It could metabolize PAHs attached to PM 2.5 , which can produce more toxic oxidation metabolites, leading to lung damage (Oesch et al, 2019). The mRNA expression levels of CYP2E1 in WT mice showed an increasing trend after PM 2.5 exposure.…”

Section: Discussionmentioning

confidence: 99%

Effects of Real-Ambient PM2.5 Exposure on Lung Damage Modulated by Nrf2−/−

Ding

Jiang

et al. 2021

Front. Pharmacol.

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Previous studies have shown that long-term exposure to fine particulate matter (PM2.5) increases the morbidity and mortality of pulmonary diseases such as asthma, chronic obstructive pulmonary disease and pulmonary emphysema. Oxidative stress and inflammation play key roles in pulmonary damage caused by PM2.5. Nuclear factor erythroid 2-related factor 2 (Nrf2) could regulate the expression of antioxidant and anti-inflammatory genes and is pivotal for protection against PM2.5-induced oxidative stress. In this study, a real-ambient exposure system was constructed with the outdoor ambient air in north China. Wild-type (WT) and Nrf2−/− (KO) mice were exposed to the real-ambient system for six weeks. After PM2.5 exposure, our data showed that the levels of inflammatory factors and malondialdehyde were significantly increased in WT and KO mice. Moreover, the lung function and pathological phenotype of the WT mice were altered but there was no obvious change in the Nrf2−/− mice. To further explore the potential molecular mechanisms, we performed RNA-sequencing. The RNA-sequence analysis results showed that the CYP450 pathway in the first ten pathways of KEGG was related to the metabolism of PM2.5. In WT and KO mice, the expression of CYP2E1 in the CYP450 pathway showed opposite trends after PM2.5 exposure. The data showed that the expression of the CYP2E1 gene in WT-PM mice increased while it decreased in KO-PM; the expression of the CYP2E1 protein showed a similar trend. CYP2E1 is primarily distributed in the endoplasmic reticulum (ER) where it could metabolize various exogenous substances attached to PM2.5 and produce highly toxic oxidation products closely related to ER stress. Consistently, the expression level of GRP94, a biomarker of ER stress, was increased in WT mice and reduced in KO mice under PM2.5 exposure. Persistent ER stress is a mechanism that causes lung damage under PM2.5 exposure. Nrf2 facilitates lung injury during PM2.5 exposure and CYP2E1 metabolism is involved in this process.

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“…This might be because of the cigarette smoking inhibiting effect on the gene expression of cytochrome P450 isoenzyme which is responsible for salbutamol first-pass metabolism and consequently reduces the metabolism of salbutamol and as a result, the unchanged salbutamol raises so the smokers' systemic bioavailability would be higher than that of the non-smokers. 61,62 However, it was found that administration of 12 puffs salbutamol pMDI using AeroChamber or CombiHaler spacers resulted in a significantly higher amount of salbutamol deposited on the filter pad in non-smokers (P < .05) compared with smokers which may be explained by the deleterious effects of smoking on the lung functions of the smokers compared with the non-smoker subjects. 63 The effect was more obvious when using the pMDI only because the dose of the pMDI is very small compared with the nebulised dose and delivered in a very short period.…”

Section: Discussionmentioning

confidence: 96%

Lung deposition and systemic bioavailability of dose delivered to smoker compared with non‐smoker COPD subjects

Mohamed

Eldin

et al. 2020

Int J Clin Pract

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Introduction Inhaled drugs are the most commonly used class of medications for COPD subjects. No studies have been performed to assess the influence of smoking on lung deposition of aerosolized medication, especially for the exacerbated COPD subject. The present study aimed to assess the influence of smoking on the lung deposition of the aerosol delivered to exacerbated COPD subjects. Methods Twenty‐four exacerbated COPD subjects using automatic continuous positive airway pressure (Auto‐CPAP), 12 smokers (six females) and 12 non‐smokers (six females) were recruited in the study. The subjects participated in the study received four salbutamol study doses; 1200 µg (12 puffs 100 µg/puff) of salbutamol emitted from pMDI canister connected to AeroChamber MV spacer; 1200 µg of salbutamol emitted from pMDI canister connected to Combihaler spacer; 1 mL of salbutamol respirable solution (5000 µg/mL) nebulized by Aerogen Solo connected to its T‐piece; and 1 mL of salbutamol respirable solution nebulized by Aerogen Solo connected to Combihaler spacer with 2 puffs salbutamol MDI (200 µg salbutamol) before nebulisation. The subjects were randomised to receive the four selected dose‐adaptor combination in a sealed envelope design on days 1, 3, 5 and 7. A washout period of 24 hours was provided between each salbutamol dosing. Auto‐CPAP was adjusted at non‐invasive ventilation mode with the integrated heated humidifier, as a source of humidity. Urine samples were provided by subjects, 30 minutes and cumulatively 24 hours post inhalation, as an index of the relative and systemic bioavailability, respectively, and aliquots were retained for salbutamol analysis using solid‐phase extraction and high‐performance liquid chromatography (HPLC). On day 2 of the study, a collecting filter was placed between the aerosol generator and the subject's mask so that the subjects would not inhale the salbutamol delivered. The same study doses and/or adapters were delivered to each subject, with filters changed with each dose‐adapter combination. Salbutamol entrained on the filter was desorbed to be analysed by the HPLC. Results Significantly higher lung deposition (30 minutes urinary salbutamol) was detected with the non‐smoker compared with smokers (P < .05). Significantly higher systemic bioavailability (pooled 24‐hour urinary salbutamol) for smokers compared with non‐smokers was found with Aerogen Solo connected to its T‐piece and CombiHaler spacer with pMDI (P < .05) only. Significantly higher amount desorbed from the ex‐vivo filter were found from pMDI with both spacers in non‐smokers (P < .05) compared with the smokers. Conclusion The study demonstrated that smoking reduced the lung deposition of inhaled salbutamol delivered by nebulizer or pMDI. However, the smoking effect on cytochrome p450 was observed to increase systemic absorption of the ingested portion of the inhaled dose. The lower lung deposition and possible higher systemic absorption should be taken into consideration while prescribing inhaled medication to COPD smokers...

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Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

Cited by 47 publications

References 416 publications

Pig Liver Esterases Hydrolyze Endocannabinoids and Promote Inflammatory Response

Pig Liver Esterases Hydrolyze Endocannabinoids and Promote Inflammatory Response

Effects of Real-Ambient PM2.5 Exposure on Lung Damage Modulated by Nrf2−/−

Lung deposition and systemic bioavailability of dose delivered to smoker compared with non‐smoker COPD subjects

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