Prostaglandin H Synthetase‐Mediated Metabolism of Dopamine: Implication for Parkinson's Disease

Michael B. Mattammal, Randy Strong, Vijaya M. Lakshmi, Hyung D. Chung, Alan H. Stephenson

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

Abstract

Abstract: Differences in prostaglandin H synthetase (PHS) activity in the substantia nigra of age‐ and post‐mortem interval‐matched parkinsonian, Alzheimer's, and normal control brain tissue were assessed. Prostaglandin E2 (PGE2, an index of PHS activity) was higher in substantia nigra of parkinsonian brain tissue than Alzheimer's or control tissue. Incubation of substantia nigra slices with arachidonic acid (AA) increased PGE2 synthesis. Dopamine stimulated PHS synthesis of PGE2. [3H]Dopamine was activated by PHS to electrophilic intermediate(s) that covalently bound to DNA, microtubulin protein, bovine serum albumin, and sulfhydryl reagents. When AA was replaced by hydrogen peroxide, PHS/H2O2‐supported binding proceeded at rates similar to those observed with PHS/AA. Indomethacin and aspirin inhibited AA‐mediated cooxidation of dopamine but not H2O2‐mediated metabolism. PHS‐mediated metabolism of dopamine was not affected by monoamine oxidase inhibitors. Substrate requirements and effects of specific inhibitors suggest cooxidation of dopamine is mediated by the hydroperoxidase activity of PHS. 32P‐postlabeling was used to detect dopamine‐DNA adducts. PHS/AA activation of dopamine in the presence of DNA resulted in the formation of five dopamine‐DNA adducts, i.e., 23, 43, 114, 70, and 270 amol/µg DNA. DNA adduct formation was PHS, AA, and dopamine dependent. PHS catalyzed cooxidation of dopamine in dopaminergic neuronal degeneration is discussed.

Original languageEnglish (US)
Pages (from-to)1645-1654
Number of pages10
JournalJournal of neurochemistry
Volume64
Issue number4
DOIs
StatePublished - Apr 1995

Keywords

  • Arachidonic acid
  • Cooxidation
  • Dopamine
  • Neurons
  • Parkinson's disease
  • Prostaglandins

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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