一氧化氮介导内毒素诱导的肝细胞色素P450功能障碍。

Nitric oxide mediates hepatic cytochrome P450 dysfunction induced by endotoxin.

作者信息

Müller C M, Scierka A, Stiller R L, Kim Y M, Cook D R, Lancaster J R, Buffington C W, Watkins W D

机构信息

Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh School of Medicine, Pennsylvania.

出版信息

Anesthesiology. 1996 Jun;84(6):1435-42. doi: 10.1097/00000542-199606000-00020.

DOI:10.1097/00000542-199606000-00020

PMID:8669685

Abstract

BACKGROUND

Animals subjected to immunostimulatory conditions (sepsis) exhibit decreased total cytochrome P450 content and decreased P450-dependent drug metabolism. Cytochrome P450 function is of clinical significance because it mediates the metabolism of some opioid and hypnotic drugs. The authors tested the hypothesis that reduced P450 function and decreased drug metabolism in sepsis are mediated by endotoxin-enhanced synthesis of nitric oxide.

METHODS

Hepatic microsomes were prepared from male Sprague-Dawley rats in nontreated rats, rats pretreated with phenobarbital and rats receiving aminoguanidine or NG-L-monomethyl-arginine alone. Nitric oxide synthesis was augmented for 12 h with a single injection of bacterial lipopolysaccharides. Nitric oxide synthase was inhibited with aminoguanidine or N(G)-L-monomethyl-arginine during the 12 h of endotoxemia in some animals. Plasma nitrite and nitrate concentrations were measured in vivo, and total microsomal P450 content, and metabolism of ethylmorphine and midazolam in vitro.

RESULTS

Administration of endotoxin increased plasma nitrite and nitrate concentrations, decreased total cytochrome P450 content, and decreased metabolism of ethylmorphine and midazolam. Inhibition of nitric oxide formation by aminoguanidine or N(G)-L-monomethyl-arginine partially prevented the endotoxin-induced effects in the nontreated and phenobarbital-treated groups. Aminoguanidine or N(G)-L-monomethyl-arginine alone did not have an effect on either total cytochrome P450 content or P450-dependent drug metabolism. Plasma nitrite and nitrate concentrations correlated significantly negatively with P450 content (nontreated r = -0.88, phenobarbital r = -0.91), concentrations of formed formaldehyde (nontreated r = -0.87, phenobarbital r = -0.95), and concentrations of midazolam metabolites (4-OH midazolam nontreated r = -0.88, phenobarbital r = -0.93, and 1'-OH midazolam nontreated r = -0.88, phenobarbital r = -0.97).

CONCLUSIONS

Altered hepatic microsomal ethylmorphine and midazolam metabolism during sepsis is mediated in large part by nitric oxide.

摘要

背景

处于免疫刺激状态（脓毒症）的动物，其细胞色素P450总量减少，且P450依赖的药物代谢降低。细胞色素P450功能具有临床意义，因为它介导某些阿片类和催眠药物的代谢。作者检验了脓毒症中P450功能降低和药物代谢减少是由内毒素增强一氧化氮合成介导的这一假说。

方法

从雄性Sprague-Dawley大鼠制备肝微粒体，这些大鼠包括未处理的大鼠、用苯巴比妥预处理的大鼠以及单独接受氨基胍或N-甲基-L-精氨酸的大鼠。单次注射细菌脂多糖使一氧化氮合成增加12小时。在一些动物内毒素血症的12小时期间，用氨基胍或N-甲基-L-精氨酸抑制一氧化氮合酶。在体内测量血浆亚硝酸盐和硝酸盐浓度，在体外测量肝微粒体P450总量以及乙基吗啡和咪达唑仑的代谢。

结果

给予内毒素增加了血浆亚硝酸盐和硝酸盐浓度，降低了细胞色素P450总量，并降低了乙基吗啡和咪达唑仑的代谢。氨基胍或N-甲基-L-精氨酸抑制一氧化氮生成部分预防了未处理组和苯巴比妥处理组中内毒素诱导的效应。单独的氨基胍或N-甲基-L-精氨酸对细胞色素P450总量或P450依赖的药物代谢均无影响。血浆亚硝酸盐和硝酸盐浓度与P450含量显著负相关（未处理组r = -0.88，苯巴比妥组r = -0.91），与生成的甲醛浓度显著负相关（未处理组r = -0.87，苯巴比妥组r = -0.95），与咪达唑仑代谢物浓度显著负相关（4-羟基咪达唑仑未处理组r = -0.88，苯巴比妥组r = -0.93；1'-羟基咪达唑仑未处理组r = -0.88，苯巴比妥组r = -0.97）。