Acetaldehyde and parkinsonism: role of CYP450 2E1

Abstract

The present review update the relationship between acetaldehyde (ACE) and parkinsonism with a specific focus on the role of P450 system and CYP 2E1 isozyme particularly. We have indicated that ACE is able to enhance the parkinsonism induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin able to damage the nigrostriatal dopaminergic pathway. Similarly diethyldithiocarbamate, the main metabolite of disulfiram, a drug widely used to control alcoholism, diallylsulfide (DAS) and phenylisothiocyanate also markedly enhance the toxin-related parkinsonism. All these compounds are substrate/inhibitors of CYP450 2E1 isozyme. The presence of CYP 2E1 has been detected in the dopamine (DA) neurons of rodent Substantia Nigra (SN), but a precise function of the enzyme has not been elucidated yet. By treating CYP 2E1 knockout (KO) mice with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the SN induced lesion was significantly reduced when compared with the lesion observed in wild-type animals. Several in vivo and in vitro studies led to the conclusion that CYP 2E1 may enhance the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice by increasing free radical production inside the dopaminergic neurons. ACE is a good substrate for CYP 2E1 enzyme as the other substrate-inhibitors and by this way may facilitate the susceptibility of dopaminergic neurons to toxic events. The literature suggests that ethanol and/or disulfiram may be responsible for toxic parkinsonism in human and it indicates that basal ganglia are the major targets of disulfiram toxicity. A very recent study reports that there are a decreased methylation of the CYP 2E1 gene and increased expression of CYP 2E1 mRNA in Parkinson's disease (PD) patient brains. This study suggests that epigenetic variants of this cytochrome contribute to the susceptibility, thus confirming multiples lines of evidence which indicate a link between environmental toxins and PD.

The Role of CYP2E1 in the Drug Metabolism or Bioactivation in the Brain

“…Clinical studies of Parkinson's disease (PD) show that environmental factors, xenobiotics, including chemicals, pesticides, and volatile solvents are the most suspected causes, all of which are substrates of CYP2E1 [105]. CYP2E1 is present in dopaminergic neurons of the substantia nigra in the same compartment as tyrosine hydroxylase [11, 42, 106, 107].…”

“…Cell cultures from CYP2E1 null mice accumulate more intracellular MPP+ than the cell culture from wild-type mice [109]. Also, MPP + accumulates inside the neurons from Knockout CYP2E1 mesencephalic cultures twice as much as wild-type embryos [105]. This evidence suggests further that CYP2E1 plays a role in MPP + storage and efflux.…”

Polymorphisms of DRD2 and DRD3 genes and Parkinson’s disease: A meta-analysis

“…The environmental hypothesis was dominant for much of the 20th century (3). Environmental factors such as encephalitis (13), oxidative stress (14), smoking and coffee (15) and environmental toxins (16) were found to be significantly associated with PD. Recent genetic studies have identified a few genetic markers of PD (17)(18)(19), however, the etiology of PD remains unclear.…”

Association of four GSTs gene polymorphisms with Parkinson disease: A meta-analysis

“…Environmental hypothesis was dominant for much of the 20th century [2]. PD was shown to be associated with environmental factors such as encephalitis [12], oxidative stress [13], smoking and coffee [14], and environmental toxins [15]. Although recent genetic studies have discovered a handful of genetic markers of PD [16][17][18], the aetiology of PD remains unknown.…”