Anesthesiology researcher studies drug metabolism in the liver

Evan Kharasch

UW researchers led by Dr. Evan D. Kharasch, professor of anesthesiology, have concluded studies that may eliminate a fatal problem associated with what is historically one of the most widely used anesthetic agents in the world.

In approximately one in 30,000 patients, the anesthetic agent halothane causes a condition known as “halothane hepatitis,” which results in swift and fatal liver damage in approximately 50 percent of cases. For four decades, this problem has been recognized in anesthesia, yet the mechanism by which it occurs has been incompletely understood.

Drug metabolism is the process by which our bodies transform and eliminate foreign compounds. Halothane is transformed in the liver into a molecule that binds to liver proteins. In most people, this process has no significance, but in a few people these liver proteins stimulate the formation of antibodies that seriously damage the liver. The reason why some patients are susceptible remains a mystery.

In a study published in the Lancet in 1996, Kharasch identified P450 2E1 as the enzyme responsible for the metabolism of halothane, which can trigger the formation of antibodies. More recently, Kharasch and colleagues have shown that they can chemically inhibit P450 2E1 from carrying out this unwanted mission by giving patients a drug called disulfiram before anesthesia.

“We manipulate the activity of the enzyme with disulfiram, known by the trade name Antabuse. We found that a single dose could ‘turn off’ P450 2E1,” he said.

The disulfiram is itself transformed in the liver into a chemical that inactivates P450 2E1 by binding to it and preventing its catalytic activity. “By turning off this enzyme we can prevent the molecular pathway leading to halothane toxification, and by extrapolation, possibly prevent halothane hepatitis,” he said.

Kharasch has identified the role of P450 2E1, and disulfiram inhibition, in the metabolism of several other volatile anesthetics. Disulfiram may also have utility beyond anesthesia. The major component in Tylenol, for instance, is also metabolized by the P450 2E1 enzyme. Inhibiting it may allow physicians to prevent liver damage in overdose cases. Kharasch said he is currently collaborating with Dr. John Slattery, professor of pharmaceutics and a member at Fred Hutchinson Cancer Research Center, who is investigating this possibility.

The knowledge researchers have gained in their work on halothane may also enable them to manipulate P450 2E1 to prevent damage to organs in workers who have been exposed to Freon, or other hazardous chemicals, in industrial accidents. “With further work, we could recommend disulfiram as a treatment for people exposed to carcinogens, or in other situations where we want to intercept the process of metabolism,” Kharasch said.

Kharasch will discuss his research in a Science in Medicine Lecture titled “Manipulating Drug Metabolism for Therapeutic Benefit: Anesthesiology and Beyond” from noon to 1 p.m. on Friday, Dec. 11, in room D-209, HSC.

Kharasch received a Ph.D. in pharmacology in 1983 and an M.D. in 1984 from Northwestern University Medical School. He joined the UW School of Medicine in 1988 as an acting assistant professor and became a full professor in 1997. ¶

Will Morton