PMID- 7532384
OWN - NLM
STAT- MEDLINE
DCOM- 19950317
LR  - 20171116
IS  - 0003-9861 (Print)
IS  - 0003-9861 (Linking)
VI  - 316
IP  - 2
DP  - 1995 Feb 1
TI  - Regulation of hepatic nitric oxide synthase by reactive oxygen intermediates and 
      glutathione.
PG  - 699-706
AB  - Regulation of induced nitric oxide synthase in rat hepatocyte primary cultures 
      was explored. Nitric oxide synthase (NOS) induction by tumor necrosis 
      factor-alpha (TNF alpha) is synergized by interferon-gamma, and both NOS activity 
      and gene expression are maximal by 10 h and maintained through 24 h. Glutathione 
      depletion by diethylmaleate, which conjugates reduced glutathione, 
      1,3-bis(chloroethyl)-1-nitrosourea (BCNU), a glutathione reductase inhibitor, or 
      buthionine sulfoxamine, a glutathione synthesis inhibitor, abolishes or reduces 
      NOS induction in TNF alpha-treated hepatocytes, whereas N-acetylcysteine has 
      little effect. Thus, reduced glutathione is critical to NOS mRNA induction and 
      activity in TNF alpha-treated hepatocytes. NOS induction in TNF alpha-treated 
      cells is reduced by rotenone, a mitochondrial complex 1 inhibitor. Concurrent 
      treatment with TNF alpha and the antioxidant, Trolox, or the iron-chelating 
      agent, desferrioxamine, also reduces NOS activity. Dithiothreitol, a thiol 
      antioxidant, reduced TNF alpha induction of NOS. Trolox and BCNU, combined, 
      blocked TNF alpha stimulation of NOS greater than either agent alone. These 
      results suggest that TNF alpha increases mitochondrial production of reactive 
      oxygen intermediates (ROI), which contributes to NOS induction. Hepatocytes 
      exposed to extracellular ROI generation through a xanthine/xanthine oxidase 
      superoxide-generating system expressed increased NOS activity and mRNA levels. 
      NOS induction by superoxide also requires reduced glutathione since 
      diethylmaleate blocks induction by xanthine/xanthine oxidase while 
      N-acetylcysteine elevates NOS expression. Thus, the generation of ROI by 
      cytokines or other physiological processes stimulates the induction of NOS and 
      this process is regulated by cellular levels of reduced glutathione.
FAU - Duval, D L
AU  - Duval DL
AD  - Cell and Molecular Pharmacology and Physiology Graduate Program, University of 
      Nevada School of Medicine, Reno 89557.
FAU - Sieg, D J
AU  - Sieg DJ
FAU - Billings, R E
AU  - Billings RE
LA  - eng
GR  - DK44755/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Arch Biochem Biophys
JT  - Archives of biochemistry and biophysics
JID - 0372430
RN  - 0 (Maleates)
RN  - 0 (RNA, Messenger)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Xanthines)
RN  - 11062-77-4 (Superoxides)
RN  - 1AVZ07U9S7 (Xanthine)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.17.3.2 (Xanthine Oxidase)
RN  - EC 1.4.- (Amino Acid Oxidoreductases)
RN  - G81WQB56OL (diethyl maleate)
RN  - GAN16C9B8O (Glutathione)
RN  - U68WG3173Y (Carmustine)
SB  - IM
MH  - Amino Acid Oxidoreductases/*biosynthesis/genetics
MH  - Animals
MH  - Carmustine/pharmacology
MH  - Gene Expression Regulation, Enzymologic/*drug effects
MH  - Glutathione/pharmacology
MH  - Interferon-gamma/pharmacology
MH  - Liver/cytology/drug effects/*enzymology
MH  - Maleates/pharmacology
MH  - Nitric Oxide Synthase
MH  - Oxidation-Reduction
MH  - RNA, Messenger/biosynthesis
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reactive Oxygen Species/pharmacology
MH  - Superoxides/metabolism
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - Xanthine
MH  - Xanthine Oxidase/pharmacology
MH  - Xanthines/pharmacology
EDAT- 1995/02/01 00:00
MHDA- 1995/02/01 00:01
CRDT- 1995/02/01 00:00
PHST- 1995/02/01 00:00 [pubmed]
PHST- 1995/02/01 00:01 [medline]
PHST- 1995/02/01 00:00 [entrez]
AID - S0003-9861(85)71093-4 [pii]
AID - 10.1006/abbi.1995.1093 [doi]
PST - ppublish
SO  - Arch Biochem Biophys. 1995 Feb 1;316(2):699-706. doi: 10.1006/abbi.1995.1093.