The role of nitric oxide in hepatic metabolism

被引:102
作者
Alexander, B [1 ]
机构
[1] Kings Coll London, Sch Med & Dent, Rayne Inst, Dept Surg, London SE5 9NU, England
关键词
nitric oxide; hepatic hemodynamics; endotoxemia; purines; cirrhosis; portal hypertension; Kupffer cells;
D O I
10.1016/S0899-9007(97)00492-9
中图分类号
R15 [营养卫生、食品卫生]; TS201 [基础科学];
学科分类号
100403 ;
摘要
Nitric oxide (NO) may regulate hepatic metabolism directly by causing alterations in hepatocellular (hepatocyte and Kupffer cell) metabolism and function or indirectly as a result of its vasodilator properties. Its release from the endothelium can be elicited by numerous autacoids such as histamine, vasoactive intestinal peptide, adenosine, ATP, 5-HT, substance P, bradykinin, and calcitonin gene-related peptide. In addition, NO may be released from the hepatic vascular endothelium, platelets, nerve endings, mast cells, and Kupffer cells as a response to various stimuli such as endotoxemia, ischemia-reperfusion injury, and circulatory shock. It is synthesized by nitric oxide synthase (NOS), which has three distinguishable isoforms: NOS-1 (ncNOS), a constitutive isoform originally isolated from neuronal sources; NOS-2 (iNOS), an inducible isoform that may generate large quantities of NO and may be induced in a variety of cell types throughout the body by the action of inflammatory stimuli such as tumor necrosis factor and interleukin (IL)-1 and -6; and NOS-3 (ecNOS), a constitutive isoform originally located in endothelial cells. Another basis for differentiation between the constitutive and inducible enzymes is the requirement for calcium binding to calmodulin in the former. NO is vulnerable to a plethora of biologic reactions, the most important being those involving higher nitrogen oxides (NO;), nitrosothiol, and nitrosyl iron-cysteine complexes, the products of which (for example, peroxynitrite), are believed to be highly cytotoxic. The ability of NO to react with iron complexes renders the cytochrome P,,, series of microsomal enzymes natural targets for inhibition by NO. It is believed that this mechanism provides negative feedback control of NO synthesis. In addition, NO may replate prostaglandin synthesis because the cyclooxygenases are other hem-containing enzymes. It may also be possible that NO-induced release of IL-1 inhibits cytochrome P(450) production, which ultimately renders the liver less resistant to trauma. It is believed that Kupffer cells are the main source of NO during endotoxemic shock and that selective inhibition of this stimulation may have future beneficial therapeutic implications. NO release in small quantities may be beneficial because it has been shown to decrease tumor cell growth and levels of prostaglandin E(2) and F(2 alpha) (proinflammatory products) and to increase protein synthesis and DNA-repair enzymes in isolated hepatocytes. NO may possess both cytoprotective and cytotoxic properties depending on the amount and the isoform of NOS by which it is produced. The mechanisms by which these properties are regulated are important in the maintenance of whole body homeostasis and remain to be elucidated. (C) Elsevier Science Inc. 1998.
引用
收藏
页码:376 / 390
页数:15
相关论文
共 185 条
[1]   MODELS OF HEPATIC DRUG CLEARANCE - DISCRIMINATION BETWEEN THE WELL STIRRED AND PARALLEL-TUBE MODELS [J].
AHMAD, AB ;
BENNETT, PN ;
ROWLAND, M .
JOURNAL OF PHARMACY AND PHARMACOLOGY, 1983, 35 (04) :219-224
[2]  
Alexander B, 1996, J PHYSIOL-LONDON, V495P, pP102
[3]  
Alexander B, 1996, J PHYSIOL-LONDON, V495P, pP97
[4]  
Alexander B, 1997, BRIT J PHARMACOL, V120, pP100
[5]   AN ISOLATED DUAL-PERFUSED RABBIT LIVER PREPARATION FOR THE STUDY OF HEPATIC BLOOD-FLOW REGULATION [J].
ALEXANDER, B ;
MATHIE, RT ;
RALEVIC, V ;
BURNSTOCK, G .
JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS, 1992, 27 (01) :17-22
[6]  
ALEXANDER B, 1994, BRIT J PHARMACOL, V111, pP248
[7]   INHIBITORS OF NITRIC-OXIDE SYNTHASE SELECTIVELY REDUCE FLOW IN TUMOR-ASSOCIATED NEOVASCULATURE [J].
ANDRADE, SP ;
HART, IR ;
PIPER, PJ .
BRITISH JOURNAL OF PHARMACOLOGY, 1992, 107 (04) :1092-1095
[8]   MODULATION OF HEPATIC MESSENGER-RNA LEVELS AFTER ADMINISTRATION OF LIPOPOLYSACCHARIDE AND DIPHTHERIA AND TETANUS TOXOIDS AND PERTUSSIS-VACCINE ADSORBED (DTP VACCINE) TO MICE [J].
ANSHER, SS ;
THOMPSON, W .
HEPATOLOGY, 1994, 20 (04) :984-991
[9]   NITRIC-OXIDE MEDIATES, AND ACETYLCHOLINE MODULATES, NEURALLY INDUCED RELAXATION OF BOVINE CEREBRAL-ARTERIES [J].
AYAJIKI, K ;
OKAMURA, T ;
TODA, N .
NEUROSCIENCE, 1993, 54 (03) :819-825
[10]   ROLE OF NITRIC-OXIDE IN PORCINE LIVER CIRCULATION UNDER NORMAL AND ENDOTOXEMIC CONDITIONS [J].
AYUSE, T ;
BRIENZA, N ;
REVELLY, JP ;
BOITNOTT, JK ;
ROBOTHAM, JL .
JOURNAL OF APPLIED PHYSIOLOGY, 1995, 78 (04) :1319-1329