New Link To Alcohol-Related Liver Damage Identified

May 01, 1997

Two decades have lapsed since the first reports that alcoholics can develop severe liver damage after taking acetaminophen, a widely used analgesic. Still, the way alcohol and acetaminophen act together in the liver to cause severe, sometimes fatal, damage is poorly understood.

Now researchers at White River Junction Veterans Administration Medical Center (VAMC) and Dartmouth Medical School (DMS) have found that more than one protein may play a major role in making acetaminophen toxic to the liver of rats administered alcohol.

Although the potential danger of acetaminophen to the liver has been widely documented, only one protein was considered the culprit in alcohol-associated damage. The recent findings implicate another, related protein, that may cause even more liver damage in individuals who consume alcoholic beverages.

The study is reported in the April issue of the journal, Toxicology and Applied Pharmacology. The team, headed by Jacqueline Sinclair, VAMC and research associate professor of biochemistry and of pharmacology and toxicology, included VAMC members Sheryl G. Wood and William J. Bement; DMS/VAMC members Vsevolod E. Kostrubsky, Juliana G. Szakacs, and Peter R. Sinclair, as well as colleagues from University of Illinois, (Elizabeth Jeffery), and Eli Lilly Research, (Steven Wrighton).

The proteins that make acetaminophen toxic to the liver are forms of cytochrome P450, a large family of proteins that facilitate excretion of chemicals from the body. Usually these proteins convert chemicals in a process called oxidation to water soluble products the body can eliminate. Occasionally, however, the chemical modifications backfire and a more toxic product results. Oxidative buildup has been associated with a variety of diseases, including cancer.

Acetaminophen was first connected to liver damage in humans more than three decades ago after cases of suicide by ingesting overdoses of the drug were reported. The problem, subsequent studies revealed, was not the parent compound itself, but the cytochrome P450s that converted acetaminophen to a toxic product. Patients can be treated for toxic overdose with an antidote that increases the level of glutathione, a chemical that helps get rid of oxidative damage.

Researchers later discovered that alcoholics can be particularly susceptible to liver failure from therapeutic or otherwise non-toxic doses of acetaminophen. Studies in experimental animals showed that the acetaminophen is only toxic if no alcohol remains in the blood when the acetaminophen is administered.

At least three separate cytochrome P450s can convert acetaminophen to a toxic form. Until recently, only one--designated CYP2E--was deemed responsible for any alcohol-related problems, because it was increased by ethanol, a key alcohol in alcoholic beverages.

The current study demonstrates that a new culprit--named CYP3A--is also linked to liver toxicity from acetaminophen in rats treated with alcohols. The work builds on previous findings by the researchers that ethanol induces the CYP3A protein in cultured liver cells from both rats and humans, as well as in whole rats.

Sinclair and her colleagues have also found that rats administered a combination of ethanol and isopentanol, the major higher chain alcohol in alcoholic beverages, and acetaminophen have even greater amounts of CYP3A, as well as more liver damage from acetaminophen.

Their studies indicate that a chemical that specifically inhibits CYP3A protects rats pretreated with ethanol from acetaminophen liver damage, suggesting that the CYP3A protein itself has a key role.

"These findings have major clinical implications," says Sinclair, "since a number of drugs increase CYP3A and may possibly increase acetaminophen toxicity. Some acetaminophen medications contain caffeine, which also stimulates CYP3A and has been shown to increase toxicity in experimental systems, so caffeine may pose an additional risk. Furthermore, the risk of liver damage from acetaminophen may prove to be higher for those who drink alcoholic beverages rich in higher chain alcohols."

Another consideration, she notes, is whether fasting has any detrimental effects. Fasting elevates both CYP2E and CYP3A, decreases glutathione levels and increases acetaminophen liver totoxicity in animals. It may prove to have similar effects in humans.

The Geisel School of Medicine at Dartmouth

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