Inhibition of the oxidative metabolism of 3,4-dihydroxyphenylacetaldehyde, a reactive intermediate of dopamine metabolism, by 4-hydroxy-2-nonenal.

摘要: Recent evidence indicates a role for oxidative stress and resulting products, e.g. 4-hydroxy-2-nonenal (4HNE) in the pathogenesis of Parkinson's disease (PD). 4HNE is known inhibitor mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme very important to dopamine (DA) metabolic pathway. DA undergoes monoamine oxidase-catalyzed deamination 3,4-dihydroxyphenylacetaldehyde (DOPAL), which metabolized primarily 3,4-dihydroxyphenylacetic acid (DOPAC) via ALDH2. The biotransformation DOPAL critical as previous studies have demonstrated this DA-derived be reactive electrophile toxic dopaminergic cells. Therefore, produced may inhibit ALDH2-mediated oxidation endogenous neurotoxin DOPAL. To test hypothesis, ALDH2 various model systems was treated with activity toward measured. Incubation human recombinant (1.5-30 microM) yielded inhibition Furthermore, rat brain lysate well isolated mitochondria also sensitive lipid peroxidation product at low micromolar, evident by decrease rate DOPAC conversion measured using HPLC. Taken together, these data indicate that micromolar inhibits DOPAC, generation represent mechanism yielding aberrant levels DOPAL, thus linking uncontrolled production relevant PD.