Abstract:
:The role of prostaglandin H synthase-1 (PHS-1) and a related model enzyme, horseradish peroxidase (HRP), in catalyzing the bioactivation of dopamine (DA) and epinephrine and their precursors and metabolites to potential neurodegenerative free radical intermediates was examined. To determine the potential contribution of PHS-dependent reactive oxygen species (ROS) formation, the neurotransmitter DA or its precursor and metabolites were incubated in vitro with purified ovine PHS-1 and calf thymus DNA. DA, its L-dihydroxyphenylalanine (L-DOPA), precursor, and its dihydroxyphenylacetic acid (DOPAC) metabolite were excellent PHS-1 substrates, resulting in PHS-1-dependent ROS formation that initiated oxidative DNA damage, selectively quantified as 8-oxo-2'-deoxyguanosine. Most substrates generated isotropic electron spin resonance (ESR) spectra with a resolved hyperfine structure attributable to ortho-semiquinone free radical intermediates upon autoxidation at pH 6, with up to a 18-fold increase via HRP-catalyzed oxidation. Remarkably, HRP-mediated oxidation of DOPAC and dihydroxymandelic acid (DHMA) produced asymmetric ESR spectra characteristic of an immobilized radical, possibly due to free radical intermediates and melanin or melanin-like polymers. These results show that the precursors and metabolites of endogenous neurotransmitters, while inactive in receptor binding assays, may actually play an important role in free radical formation. Additionally, ROS generated by PHS-catalyzed bioactivation produce oxidative DNA damage in the central nervous system, which may initiate neurodegeneration associated with aging.
journal_name
Chem Res Toxicoljournal_title
Chemical research in toxicologyauthors
Gonçalves LL,Ramkissoon A,Wells PGdoi
10.1021/tx800423ssubject
Has Abstractpub_date
2009-05-01 00:00:00pages
842-52issue
5eissn
0893-228Xissn
1520-5010journal_volume
22pub_type
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