One reason Tylenol - the reliever of colds, cough, allergy, flu, pain and arthritis - is a household name is that it's sold over the counter: no doctor's prescription needed. The multipurpose analgesic drug comes in liquid drops and chewable caplets. Tylenol's active ingredient is acetaminophen, which elevates the brain's pain threshold and reduces fever.
Tylenol is packaged for medical purpose and consumers' age level, from grape- and cherry-flavored "Infant's Tylenol" to adult "Extra-Strength Tylenol." The baby and toddler versions pack 160 milligrams of acetaminophen. Extra-strength delivers 500 mg, and maximum arthritis strength, 650 mg.
What is Tylenol's guilty secret? A "professional information" package insert warns physicians that "acetaminophen in massive overdosage may cause hepatic toxicity in some patients." However, an editorial in the current issue of Science, dated Oct. 11, 2002, reports: "Every year in the U.S. overdoses of the painkiller [Tylenol] cause acute liver failure in as many as 800 people, one-third of whom die as a result, usually, of centrilobular necrosis." And other sources note that acetaminophen toxicity is the No. 1 cause of hospital admissions for liver failure in this country. The overdoses cause liver damage because certain enzymes break the painkiller down into toxic byproducts.
Wherefore, last week an FDA advisory committee urged the agency to recommend that medicines containing acetaminophen, sold under the brand name Tylenol, carry stronger warnings about the dangerous side effects. That action coincides with a paper in the same Oct. 11 issue of Science. Its title: "Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR." Its senior author is molecular and cellular biologist David Moore, at Baylor College of Medicine in Houston.
"Our work," he stated, "explains an important but unexpected component of acetaminophen toxicity and adds a new mechanism to the process. It also suggests a new approach for treating hepatotoxicity. A protein known as CAR [constitutive androstane receptor]," he added, "has been shown to regulate liver toxicity caused by the common pain reliever acetaminophen in studies that point the way to new treatment for poisoning with similar compounds. When a person takes acetaminophen," Moore explained, "the liver produces small amounts of a potentially harmful compound called NAPQ1 [N-acetyl-p-benzoquinone imine]. Particularly at high doses, cytochrome P-450 9 [CYP] enzymes convert acetaminophen to a reactive quinone form that causes production of reactive oxygen species. Normally," he continued, "the liver uses another chemical called glutathione to quickly neutralize NAPQ1. The problem occurs when you run out of glutathione."
CAR's Good Effects Can Turn 180 Degrees
But that's just the beginning of the toxic mechanism. CAR is a receptor that regulates the response of the liver to drugs and other foreign compounds. When it is activated, the liver increases its ability to modify such compounds and eliminate them from the body. This is normally a protective response. In some cases, however, it can also result in harmful effects - such as increasing the production of toxic byproducts like NAPQ1.
A clue that CAR may be implicated in acetaminophen toxicity came a few years ago. The sedative drug phenobarbital increases susceptibility to acetaminophen damage because it fosters production of two enzymes in the CYP family that convert the analgesic to the highly toxic NAPQ1. The cell normally eliminates NAPQ1 by tying it up with the detoxifying glutathione. But if NAPQ1 production outstrips the glutathione supply, cell damage takes place.
Moore and his co-authors generated a knockout mouse that lacked CAR and showed that the receptor was critical to the medication's toxicity. "We found out," he recounted, "that high doses of acetaminophen activate CAR, which then in turn activates target genes that increase toxicity. This generates a vicious cycle in which acetaminophen actually worsens its own toxicity. Because of the absence of this cycle, KO mice without CAR are partially resistant to high doses of acetaminophen. When CAR-positive mice were given a drug called androstanol, which reverses the receptor's activity, they were even more resistant to toxic effects of the analgesic."
Inactivating the human counterpart of the CAR gene before an overdose isn't a likely therapeutic strategy. But Moore's team found that the CAR-inhibiting androstanol protected mice against liver damage even after exposure to the painkiller. It provided 100 percent protection one hour later, 50 percent after three hours.
Different species can vary significantly in their reactions to foreign chemicals, the Science editorial pointed out. To determine whether the human CAR receptor responds to acetaminophen the same way the mouse version does the Baylor group created transgenic mice whose liver cells contained only human CAR. When these humanized animals received phenobarbital or acetaminophen, their livers showed damage similar to that in normal mice. Activation of either mouse or human CAR by appropriate inducers, including acetaminophen itself, increased toxicity. The Science paper remarked, "Fatal outcomes have been reported for the combination of phenobarbital and Tylenol in humans." It concluded that "CAR is a central mediator of acetaminophen toxicity in mice and potentially also in humans."
Mice Aren't Humans; Ergo, No Therapy In View
The current treatment for Tylenol overdose relies on a compound that replenishes the missing glutathione in the liver. It's effective if given in good time. Blocking CAR," Moore said, "would provide a completely different approach to acetaminophen toxicity, and possibly to the toxicity of other agents, for which no drug treatment is currently available. The results described here," he went on, "suggest a new strategy based on CAR inverse agonists.
"A potential problem with this strategy is that those inverse agonists that potentially inhibit murine CAR have only a very limited effect on the human receptor. However, it is an exciting possibility that the identification of potent and specific new inverse agonists for human CAR may provide a clinically useful means to treat toxicity of acetaminophen and potentially other hepatotoxic agents. Unfortunately, there is no drug yet that efficiently blocks the human form of CAR. Studies to identify such an inhibitor," Moore concluded, "are under way."