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

Abstract

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.

Decreased expression of hepatic cytochrome P450 1A2 (CYP1A2) in a chronic intermittent hypoxia mouse model

“…Decreased expression of hepatic cytochrome P450 1A2 (CYP1A2) in a chronic intermittent hypoxia mouse model were down-regulated, while CYP3A6 and P-glycoprotein were up-regulated, Li et al demonstrated that the activity of hepatic CYP family, CYP1A2 rather than CYP2C9 and CYP2C19, were decreased after rat were subjected to highaltitude hypoxia (5). A human study with 12 volunteers exposed to altitude-induced hypoxia found that the activity of CYP2D6 and CYP3A4 was slightly reduced (6).…”

“…CIH easily triggers systemic inflammation, oxidative stress, endothelial damage, and metabolic abnormalities (7). Numerous data demonstrated the impact of sustained hypoxia on hepatic CYP and drug metabolism (3)(4)(5)32). Patients with chronic sustained hypoxia were advised to adjust the dosage of drugs (6).…”

Pharmacokinetics of Lidocaine Hydrochloride Metabolized by CYP3A4 in Chinese Han Volunteers Living at Low Altitude and in Native Han and Tibetan Chinese Volunteers Living at High Altitude

“…Recently, Rahman and Thomas [27] found that exposure to hypoxia for 2 weeks caused significant decreases in hepatic CY-P1A mRNA and protein levels compared with CYP1A levels in fish in normoxic-condition in vivo studies. Our recent study found that acute and CHH caused significant decreases in the activity, protein and mRNA expression of rat CYP1A2 in vivo, and that CHH upregulated the activity, protein and mRNA expression of rat CYP2D6 [28] .…”

Effect of X‐ray irradiation on pharmacokinetics of irinotecan hydrochloride and expression of CES1 and CYP3A1 in rats

“…The liver tissues were immediately frozen in liquid nitrogen. The liver microsomes were prepared using differential centrifugation according to our previous reports . Briefly, liver samples were thawed and weighed, and two volumes of ice‐cold homogenization medium (50 mmol/L Tris‐HCl buffer at pH 7.4 containing 0.25 m sucrose) were then added.…”

“…The expression of CES1 and CYP3A1 was determined by ELISA according to our previous reports . Briefly, to establish a bland well without any solution, 50 μL of standard and 40 μL of sample diluted solution were added to standard and sample wells with a biotin‐conjugated antibody specific to CES1 and CYP3A1, respectively.…”