Preferential effects of nicotine and 4-(N-methyl- N-nitrosamino)-1-(3-pyridyl)-1-butanone on mitochondrial glutathione S-transferase A4-4 induction and increased oxidative stress in the rat brain

Shripad V. Bhagwat, C. Vijayasarathy, Haider Raza, Jayati Mullick, Narayan G. Avadhani

Research output: Contribution to journalArticlepeer-review

117 Citations (Scopus)

Abstract

We have investigated the in vivo effects of the tobacco-specific toxins nicotine and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on antioxidant defense systems in the mitochondrial, microsomal, and cytosolic compartments of rat brain, lung, and liver. Nicotine induced maximum oxidative stress in brain mitochondria, as seen from a 1.9-fold (P < 0.001) increase in thiobarbituric acid-reactive substance (TBARS) and a 2-fold (P < 0.001) increase in glutathione S-transferase (GST) A4-4 (also referred to as rGST 8-8) activities. These changes were accompanied by a 25-40% increase in reactive oxygen species and a 20-30% decrease in alcohol dehydrogenase activities. The 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-l-butanone-induced oxidative damage was apparent in the microsomal fraction of brain, lung, and liver, and it also increased 4-hydroxynonenal specific GST A4-4 activity in the brain and lung mitochondrial matrix fraction. The levels of microsomal thiobarbituric acid reactive substance, cytochrome P4502E1 activity, and reactive oxygen species were also increased significantly (P < 0.001) in all tissues. Both of these toxins induced the level of GST A4-4 mRNA in the brain, while they caused a marked reduction in the liver GST A4-4 mRNA pool. Additionally, the brain mitochondrial matrix showed a markedly higher level of 4-hydroxynonenal specific GST activity and mGST A4-4 antibody-reactive protein than did the cytosolic fraction. In conclusion, the present study provides evidence for the occurrence of GST A4-4 enzyme activity in mammalian mitochondria, in addition to demonstrating that both mitochondria and microsomes are intracellular targets for nicotine- and NNK-induced organ toxicity. Copyright (C) 1998 Elsevier Science Inc.

Original languageEnglish
Pages (from-to)831-839
Number of pages9
JournalBiochemical Pharmacology
Volume56
Issue number7
DOIs
Publication statusPublished - Oct 1 1998
Externally publishedYes

Keywords

  • Brain mitochondria
  • Glutathione S-transferase
  • Lipid peroxidation
  • NNK
  • Nicotine
  • Oxidative stress
  • mRNA induction

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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