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. 2022 Apr 29:2022:2782702.
doi: 10.1155/2022/2782702. eCollection 2022.

Intermittent Hypoxia Inhibits Hepatic CYP1a2 Expression and Delays Aminophylline Metabolism

Xiao-Bin Zhang  1 , Xiao-Yang Chen  2 , Kam Yu Chiu  1 , Xiu-Zhen He  1 , Jian-Ming Wang  3 , Hui-Qing Zeng  1 , Yiming Zeng  2
Affiliations

Intermittent Hypoxia Inhibits Hepatic CYP1a2 Expression and Delays Aminophylline Metabolism

Xiao-Bin Zhang et al. Evid Based Complement Alternat Med. .

Abstract

Purpose: In this study, we aimed to determine the effects of intermittent hypoxia (IH) on hepatic cytochrome P450 1A2 (CYP1A2) expression and the pharmacokinetics of CYP1A2-mediated aminophylline and warfarin in vitro and in a rabbit model of obstructive sleep apnea.

Materials: Human normal liver (LO-2) cells were exposed to 30 min each of 1%, 1-21%, 21%, and 21-1% O2, and then, CYP1A2 expression and drug concentrations were analyzed. We compared the pharmacokinetic parameters of drugs administered to normoxic rabbits and those exposed to 10 min of IH during which the oxygen level fluctuated from 21% to 8%-10% (n = 10 per group).

Result: s. The expression of CYP1A2 protein in vitro was significantly reduced in the IH compared with the normoxic cells (0.56 ± 0.11 vs. 1.27 ± 0.17, p < 0.001). Aminophylline was more abundant in cell culture supernatants after 48 h of IH than in those under normoxia. The T 1/2, AUC0-24 h, and Ke values for aminophylline were significantly higher in the IH group.

Conclusion: Intermittent hypoxia inhibits hepatic CYP1A2 expression and delays aminophylline metabolism, suggesting that the impact of IH on the expression of CYP enzymes should be closely monitored in clinical practice.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Effects of IH, aminophylline, and warfarin on liver cell viability. IH exposure for 48 h decreased viability (OD450 value) of cells incubated with aminophylline (a) and (b) and warfarin (c) and (d). IH, intermittent hypoxia; OD, optical density.
Figure 2
Figure 2
Effects of IH on liver cell apoptosis. Apoptosis rates were significantly higher in IH than in normoxic liver cells at 24 and 48 h (p < 0.05 and p < 0.001, respectively). IH, intermittent hypoxia; PI, propidium iodide.
Figure 3
Figure 3
Effects of IH on CYP1A2 and HIF-1α expression in vitro and in vivo.
Figure 4
Figure 4
Influence of IH on expression of CYP enzymes responsible for warfarin metabolism. Western blots show no differences in CYP2C9, CYP2C19, and CYP3A4 expression between normoxic and IH groups (p < 0.05 for all). Expression of CYP enzymes is shown relative to that of β-actin.
Figure 5
Figure 5
Effects of IH on aminophylline and warfarin concentrations in vitro. (A, B) Concentrations of aminophylline and warfarin did not differ between normoxic and IH LO-2 cells after 24 h, but that of aminophylline after 48 h was significantly higher in the IH cells than that in the normoxic cells (125.83 ± 12.84 vs. 64.33 ± 16.61 μmol/L, p < 0.001). The warfarin concentration remained similar between the IH and normoxic cells at 48 h (190.50 ± 14.88 vs. 200.00 ± 14.63 μmol/L, p < 0.05). IH, intermittent hypoxia.
Figure 6
Figure 6
Mean plasma concentration-time curves for aminophylline and warfarin in the rabbit model of IH. (a) Time curves of mean plasma aminophylline concentrations in IH and normoxic rabbits intravenously injected with 4 mg/kg aminophylline. (b) Time curves of mean plasma warfarin concentrations in IH and normoxic rabbits orally administered with 0.2 mg/kg warfarin. IH, intermittent hypoxia.
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