N-Acetylcysteine–A Biochemical Triumph
When a diagnosis is made of acetaminophen overdose in an emergency room, out comes the N-acetylcysteine (NAC). This is not a rare occurrence because acetaminophen is a widely used pain killer and often people think that if a little is good, more must be better. It isn’t. Especially when combined with alcohol. That’s not a rare occurrence either. Drink, get a headache, take a pill.
Now for a touch of biochemistry. When the body confronts a foreign substance, various detoxication processes swing into action. In the case of acetaminophen, enzymes start the process by initiating conversion into N-acetyl-p-benzoquinone imine (NAPQI), which is then eliminated by reaction with one of the body’s powerful antioxidants, glutathione. However, an overdose of acetaminophen leads to more NAPQI than glutathione can handle. And that’s a problem because NAPQI damages the liver. What’s the answer? Increase the supply of glutathione. Easier said than done.
Glutathione is composed of three amino acids, commonly referred to as a tripeptide. It cannot be taken orally because it is rapidly broken down in the digestive tract to its components, glutamic acid, glycine and cysteine. It is possible, however, to stimulate the synthesis of glutathione within cells where it is needed. In general there is an ample supply of glycine and glutamic acid from the diet but cysteine is in short supply. So why not just take cysteine pills? Because it is unpalatable and poorly absorbed. But the closely related substance, N-acetylcysteine works well. It is readily absorbed and is quickly converted in cells into cysteine which in turn boosts glutathione production. When NAC is administered intravenously it works even faster to counter acetaminophen overdose. And that’s why no emergency room is without it.
Lately, psychiatrists have also taken a keen interest in NAC since oxidative stress may play a role in some psychiatric disorders in which case increased levels of glutathione may be helpful. Several clinical investigations of NAC have been carried out on patients suffering from schizophrenia, bipolar disorder, cocaine dependence, depressive and anxiety disorders as well as obsessive-compulsive disease. Although there have been some promising results much more work needs to be done to confirm dosing ranges and duration of treatment.
In addition to healthcare providers, athletes have also turned to NAC as supplements. The rationale is that exercise induces oxidative stress which in turn impairs performance. Indeed, some studies have suggested that increasing glutathione availability improves exercise performance in both rats and in humans. While the evidence is not robust, and safety has not been proven, many athletes are willing to experiment with NAC supplements. There could be a price to pay. A recent study on mice at the University of Virginia found that NAC could lead to pulmonary arterial hypertension. Perhaps future research will conclusively demonstrate a role for N-acetylcysteine in the treatment of mental illness and athletic performance, but for now it is only in acetaminophen overdose that that the use of NAC is well established. And that would not have happened without a proper understanding of the biochemistry involved.