Premium
Prostaglandin H Synthetase‐Mediated Metabolism of Dopamine: Implication for Parkinson's Disease
Author(s) -
Mattammal Michael B.,
Strong Randy,
Lakshmi Vijaya M.,
Chung Hyung D.,
Stephenson Alan H.
Publication year - 1995
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1995.64041645.x
Subject(s) - dopamine , substantia nigra , chemistry , dopaminergic , 3,4 dihydroxyphenylacetic acid , biochemistry , prostaglandin , medicine , endocrinology , homovanillic acid , biology , serotonin , receptor
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 E 2 (PGE 2 , 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 PGE 2 synthesis. Dopamine stimulated PHS synthesis of PGE 2 . [ 3 H]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/H 2 O 2 ‐supported binding proceeded at rates similar to those observed with PHS/AA. Indomethacin and aspirin inhibited AA‐mediated cooxidation of dopamine but not H 2 O 2 ‐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. 32 P‐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.