Acetaminophen Overpowers Some Cell-Protecting Genes


Long Island University-Brooklyn Professor Discovers Acetaminophen Overpowers Some Cell-Protecting Genes

Brooklyn, NY--Acetaminophen is one of the top over-the-counter analgesic and anti-fever medications. Notwithstanding its therapeutic value, however, decades of research shows that very high doses of the drug can cause liver cell death, especially when combined with alcohol, by adversely affecting targets within the cell in little understood ways.

Research done by Professor Sidhartha D. Ray of Long Island University's Arnold & Marie Schwartz College of Pharmacy and Health Sciences in Brooklyn has shed some new light on acetaminophen's mechanisms of action on the molecular level. He has demonstrated for the first time the powerful impact of acetaminophen on the expression of the BCL-XL protein, which inhibits cell death in the liver.

"This is one step forward in discovering how acetaminophen causes liver damage," said Dr. Ray, an Indian-born resident of Milltown, NJ, who (with co-author Nilameni Jena of Massachusetts Institute of Technology) published his findings in the January issue of the Archives of Toxicology. Ray and Jena claim "we are the first to report acetaminophen's effects at the genetic level."

Ray exposed mice to hepatoxic (toxic to the liver) doses of acetaminophen and studied its effects on the integrity of DNA and various cell death-regulating genes. To his utter surprise he found that the expression of BCL-XL, an important cell death inhibitory gene, was significantly modified and inactivated by acetaminophen. "It was not known before whether acetaminophen could interact at the genetic level, " he says. "Now that we know, we can design antidotes to counteract acetaminophen toxicity more effectively. "

Ray is a dedicated researcher who for a decade and a half has studied acetaminophen toxicity. The drug has been used as a powerful tool to study the mechanisms of liver injury. In 1997, 72,000 cases of acetaminophen toxicity were reported to poison control centers, of which 560 were life threatening.

Ray explains that the drug is known to activate two forms of cell death in the liver--apoptosis (programmed or beneficial cell death that occurs during cell renewal and the aging process) and necrosis (accidental or unprogrammed death of cells in response to physical injury or exposure to toxic substances). "Our findings advance the understanding of the classical mechanisms of acetaminophen-induced liver injury," he says.

"Apoptosis is a very hot area," says Ray. In the past two decades, according to him, there have been 33,000 papers--"every five hours a paper is published on apoptosis." He contributed a chapter on "Cell Death and Apoptosis" in the just published book General and Applied Toxicology (Macmillan, 1999). Because apoptosis is natural cell death, it has tremendous implications in cancer research.

A professor with Long Island University since 1994, Dr. Ray presented some of his other findings at the genetic level on the anticancer agent Doxorubicin at the annual meeting of the Society of Toxicology in Philadelphia in March. He also attended the American Association for Cancer Research meeting in San Francisco in April, where he discussed how dimethylnitrosamine-induced liver cancer is attenuated by exposure to grape-seed extract. He has also studied how the diuretic Furosemide and aliphatic alcohols (methanol, ethanol, etc) can induce liver cell apoptosis.

One of the largest schools of its kind in the country, the Arnold & Marie Schwartz College of Pharmacy and Health Sciences, on Long Island University's Brooklyn Campus, educates nearly one third of the pharmacists in New York State and many who find careers elsewhere. The school recently added Pharm.D. and Ph.D. degrees to its curriculum. Long Island University, a doctoral degree-granting institution tracing its roots to 1886, is the eighth largest private university in the United States. Its downtown Brooklyn Campus offers more than 11,000 students 127 programs in over 50 undergraduate and a comparable number of graduate fields. It is located at the corner of Flatbush Avenue Extension and DeKalb Avenue in Downtown Brooklyn.

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