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

被引：41

作者：

Li, Xiangyang ^{[1
]}

Wang, Xuejun ^{[2
]}

Li, Yongping ^{[1
]}

Yuan, Ming ^{[1
]}

Zhu, Junbo ^{[1
]}

Su, Xiaodong ^{[1
]}

Yao, Xingchen ^{[1
]}

Fan, Xueru ^{[1
]}

Duan, Yabin ^{[1
]}

机构：

[1] Qinghai Univ, Coll Med, Dept Pharm, Xining 810001, Peoples R China

[2] Red Cross Hosp Qinghai, Xining, Peoples R China

来源：

PHARMACOLOGY | 2014年 / 93卷 / 1-2期

基金：

中国国家自然科学基金;

关键词：

High altitude; Hypoxia; Cytochrome P450; N-acetyltransferase; 2; Activity; Expression; MALE CHINESE VOLUNTEERS; ACUTE MODERATE HYPOXIA; DRUG-METABOLISM; HEPATIC CYTOCHROME-P450; DOWN-REGULATION; UP-REGULATION; OXYGEN; PHARMACOKINETICS; INFLAMMATION; ZONATION;

D O I：

10.1159/000358128

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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. (C) 2014 S. Karger AG, Basel

引用

页码：76 / 83

页数：8

共 38 条

[1]

Arancibia A, 2003, INT J CLIN PHARM TH, V41, P200

[2] Cytochrome P450 inactivation by serum from humans with a viral infection and serum from rabbits with a turpentine-induced inflammation: the role of cytokines [J].

Bleau, AM ;

Levitchi, MC ;

Maurice, H ;

du Souich, P .

BRITISH JOURNAL OF PHARMACOLOGY, 2000, 130 (08) :1777-1784

[3] HYPOXIC LIVER-INJURY AND THE AMELIORATING EFFECTS OF FRUCTOSE - THE GLUCOSE PARADOX REVISITED [J].

BRASS, CA ;

CRAWFORD, JM ;

NARCISO, J ;

GOLLAN, JL .

AMERICAN JOURNAL OF PHYSIOLOGY, 1992, 263 (03) :G293-G300

[4]

Duplain H, 2007, Rev Med Suisse, V3, P1766

[5] GENETICALLY-DETERMINED DIFFERENCES IN DRUG-METABOLISM AS A RISK FACTOR IN DRUG TOXICITY [J].

EICHELBAUM, M ;

KROEMER, HK ;

MIKUS, G .

TOXICOLOGY LETTERS, 1992, 64-5 :115-122

[6] Effect of hypoxia on cytochrome P450 activity and expression [J].

Fradette, C ;

du Souich, P .

CURRENT DRUG METABOLISM, 2004, 5 (03) :257-271

[7] Hypoxia-induced down-regulation of CYP1A1/1A2 and up-regulation of CYP3A6 involves serum mediators [J].

Fradette, C ;

Bleau, AM ;

Pichette, V ;

Chauret, N ;

du Souich, P .

BRITISH JOURNAL OF PHARMACOLOGY, 2002, 137 (06) :881-891

[8] Animal models of acute moderate hypoxia are associated with a down-regulation of CYP1A1, 1A2, 2B4, 2C5, and 2C16 and up-regulation of CYP3A6 and P-glycoprotein in liver [J].

Fradette, Caroline ;

Batonga, Joelle ;

Teng, Shirley ;

Piquette-Miller, Micheline ;

du Souich, Patrick .

DRUG METABOLISM AND DISPOSITION, 2007, 35 (05) :765-771

[9] High-altitude illness [J].

Gallagher, SA ;

Hackett, PH .

EMERGENCY MEDICINE CLINICS OF NORTH AMERICA, 2004, 22 (02) :329-+

[10]

Guengerich F.P., 1995, CYTOCHROME P450 STRU, P473

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