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zondag 29 januari 2012

Acetaminophen depletes glutathion

Acetaminophen = paracetamol

Acetaminophen: The Case for a Link to Neurodegenerative Diseases

Acetaminophen either decreases or depletes the endogenous anti-oxidant glutathione in mammalian cells. Without the protective effects of glutathione, mammalian cell damage or cell death occurs. Neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease and disorders of retinal cells, such as age associated macular degeneration, are due at least in part to cellular damage induced by free radicals and oxidative stress. By reducing or depleting neuronal and retinal glutathione, acetaminophen might trigger, accelerate or otherwise worsen these diseases.

Presentation of the Hypothesis

Although acetaminophen lacks the gastric toxicity and anti-platelet activity of aspirin and other classic NSAIDs, it is well known to have hepatotoxicity [7]. Chronic long term acetaminophen use increases the risk of liver failure and acute overdosage can cause fulminant liver necrosis and failure [7]. The mechanism by which acetaminophen causes liver toxicity is probably due to depletion of glutathione by this drug [7]. The hepatic cells are then unable to neutralize the toxic effects of peroxides, superoxide species and free radicals which are generated during the normal course of metabolism.

Neurons within the CNS are very metabolically active, moreover, there is evidence that the glutathione levels within CNS neurons fall with advancing age [8-10]. Others have postulated a role for oxidative stress in neurodegenerative diseases, including Parkinson’s’ disease and Alzheimer’s disease [8, 9].

Given the ability of acetaminophen to cross the blood-brain barrier and its glutathione reducing activity, I postulate that the use of acetaminophen amplifies the toxic effects of oxidative stress on CNS neurons as well as retinal cells and their neuronal network. Further, I hypothesize that the reduction of glutathione levels due to natural aging causes increased sensitivity to the toxic effects of acetaminophen in the elderly. Acetaminophen may thus be a direct cause of neurodegenerative and oculodegenerative diseases of the retina or may be a co-factor in the development and the acceleration of neuronal damage and loss in these diseases.

In the United States, approximately 2000 cases of acute liver failure occur annually and drugs account for over 50% of them (39% are due to acetaminophen, 13% are idiosyncratic reactions due to other medications).

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