Cytochrome P450 enzyme-mediated drug metabolism at exposure to acute hypoxia (corresponding to an altitude of 4,500�m)

Streit, Marcus R.; Göggelmann, Christoph; Dehnert, Christoph; Burhenne, Jürgen; Riedel, K.; Menold, Elmar; Mikus, Gerd; Bärtsch, Peter; Haefeli, Walter E.

doi:10.1007/s00228-004-0886-1

Cited by 25 publications

(12 citation statements)

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“…[ 26 ] In animal experiments, CYP1A1 and CYP1A2 protein expression was decreased in the liver after 24 h of hypoxic exposure, whereas expression of the CYP3A6 protein was increased. [ 18 ] Although the effects of hypoxemia on the expression of CYPs depend on the cell type, IH obviously causes a general decrease in the expression levels in the liver,[ 24 ] which is consistent with our findings.…”

Section: Discussionsupporting

confidence: 91%

“…Although there is no clear explanation as to the exact mechanism of how IH influences CYP expression, it has been reported that inflammatory factors may have an influence on the transcription of CYPs. [ 18 ] As shown in our study, the increased expression of IL-1β may inhibit the transcription of CYPs and cause a decrease in their expression.…”

Section: Discussionmentioning

confidence: 65%

“…In addition, the synthesis and nuclear translocation of these receptors correlated negatively with NF-κB nuclear translocation. [ 17 18 ] In our experiment, we found that the hepatic mRNA expression levels of PXR and CAR remained unchanged in the IH group compared with that in the control group [Figure 3b and 3c ]. However, GR expression was obviously diminished in the IH group (0.056 ± 0.012 vs. 0.032 ± 0.005, P = 0.035) [ Figure 3d ].…”

Section: R Esultsmentioning

confidence: 69%

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Hepatic Cyp1a2 Expression Reduction during Inflammation Elicited in a Rat Model of Intermittent Hypoxia

Shi

Wang

et al. 2017

Chinese Medical Journal

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Background:Intermittent hypoxia (IH) is a key element of obstructive sleep apnea (OSA) that can lead to disorders in the liver. In this study, IH was established in a rat model to examine its effects on the expression of hepatic cytochrome P450 (CYP) and CYP regulators, including nuclear receptors.Methods:Hematoxylin and eosin staining was conducted to analyze the general pathology of the liver of rats exposed to IH. The messenger RNA (mRNA) expression levels of inflammatory cytokines, CYPs, nuclear factor-κB (NF-κB), and nuclear factors in the liver were measured by quantitative reverse transcription polymerase chain reaction.Results:We found inflammatory infiltrates in the liver of rats exposed to IH. The mRNA expression level of interleukin-1beta was increased in the liver of the IH-exposed rats (0.005 ± 0.001 vs. 0.038 ± 0.008, P = 0.042), whereas the mRNA expression level of Cyp1a2 was downregulated (0.022 ± 0.002 vs. 0.0050 ± 0.0002, P = 0.029). The hepatic level of transcription factor NF-κB was also reduced in the IH group relative to that in the control group, but the difference was not statistically significant and was parallel to the expression of the pregnane X receptor and constitutive androstane receptor. However, the decreased expression of the glucocorticoid receptor upon IH treatment was statistically significant (0.056 ± 0.012 vs. 0.032 ± 0.005, P = 0.035).Conclusions:These results indicate a decrease in expression of hepatic CYPs and their regulator GR in rats exposed to IH. Therefore, this should be noted for patients on medication, especially those on drugs metabolized via the hepatic system, and close attention should be paid to the liver function of patients with OSA-associated IH.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 65%

Section: R Esultsmentioning

confidence: 69%

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Hepatic Cyp1a2 Expression Reduction during Inflammation Elicited in a Rat Model of Intermittent Hypoxia

Shi

Wang

et al. 2017

Chinese Medical Journal

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“…These small changes in the activity of CYP2D6 and CYP3A4 suggest that acute hypoxia has no clinically signifi cant effects on CYP enzymes in humans. Another study confi rms this, examining the effect of acute hypoxia on CYP1A2 (theophylline metabolism) and CYP3A4 (verapamil) in 20 subjects in a normobaric hypoxic chamber [ 57 ]. Subjects were randomly allocated to receive intravenous infusions of theophylline (6 mg/kg) or verapamil (5 mg) in a crossover design, with exposure to normoxia and hypoxia (12 % oxygen) corresponding to the ambient PaO 2 at 4,500 m. Acute hypoxia did not alter the pharmacokinetics of theophylline ( T 1/2 ± SD: 9.29 ± 1.77 vs. 9.39 ± 1.40 (hypoxia)), verapamil (2.00 ± 0.98 vs. 1.79 + 0.58), or their principal metabolites .…”

Section: Hepatic Functionmentioning

confidence: 95%

Gastrointestinal Function

Hamad¹,

Travis²

2013

High Altitude

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“…However, animal studies measuring the effect of hypoxia on the activity or levels of P450 enzymes in the liver have yielded conflicting results. Some studies have shown that hypoxia did not impair the metabolism mediated by cytochrome P450 [8,9]. …”

Section: Introductionmentioning

confidence: 99%

Effect of Exposure to Acute and Chronic High-Altitude Hypoxia on the Activity and Expression of CYP1A2, CYP2D6, CYP2C9, CYP2C19 and NAT2 in Rats

Wang

et al. 2014

Pharmacology

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We investigated the effect of exposure to acute and chronic high-altitude hypoxia (AHH and CHH) on the activity and expression of CYP1A2, CYP2D6, CYP2C9, CYP2C19 and NAT2 in rats. The rats were divided into plain (400 m), acute middle-altitude hypoxia (2,800 m), chronic middle-altitude hypoxia (2,800 m), AHH (4,300 m) and CHH (4,300 m). After probe drugs had been orally administered to the rats of the 5 groups, the serum or urine concentration of the probe drug and its metabolite was determined by reversed-phase HPLC. The activity of cytochrome P450 isozyme and NAT2 was evaluated by the ratio of the metabolite to the probe drug. The ELISA and real-time PCR were used to analyze the protein and mRNA expression of cytochrome P450 isozyme and NAT2, respectively. AHH and CHH caused significant decreases in the activity and protein and mRNA expression of rat CYP1A2 in vivo. AHH downregulates the activity and mRNA expression of rat NAT2 in vivo, and CHH upregulates the activity and protein and mRNA expression of rat CYP2D6. AHH and CHH did not change the expression of CYP2C9 and CYP2C19 in rats. This study found significant changes in the activity and protein and mRNA expression of CYP1A2, CYP2D6 and NAT2 in rats in the special environment of high-altitude hypoxia.

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Cytochrome P450 enzyme-mediated drug metabolism at exposure to acute hypoxia (corresponding to an altitude of 4,500�m)

Cited by 25 publications

References 36 publications

Hepatic Cyp1a2 Expression Reduction during Inflammation Elicited in a Rat Model of Intermittent Hypoxia

Hepatic Cyp1a2 Expression Reduction during Inflammation Elicited in a Rat Model of Intermittent Hypoxia

Gastrointestinal Function

Effect of Exposure to Acute and Chronic High-Altitude Hypoxia on the Activity and Expression of CYP1A2, CYP2D6, CYP2C9, CYP2C19 and NAT2 in Rats

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