2/05/2010 - Severe muscle injuries — such as those suffered by victims of earthquakes, car accidents and explosions — can cause life-threatening kidney damage.
Treatment has been limited to intravenous fluids and dialysis, but a new study suggests that the commonly used pain reliever acetaminophen (the active ingredient in Tylenol) may protect the kidneys from damage.
An international research team led by investigators at Vanderbilt University Medical Center reports this week in the Proceedings of the National Academy of Sciences that acetaminophen prevented oxidative damage and kidney failure after muscle injury in a rat model. The findings support further investigation of the drug's effects in patients with severe muscle injuries.
“This is a novel application of acetaminophen,” said the study's lead author, Olivier Boutaud, Ph.D., research associate professor of Pharmacology. The idea “came from two groups working on different things and getting together to create something new,” he said.
The story began more than a decade ago.
L. Jackson Roberts II, M.D., professor of Pharmacology and Medicine, and collaborators were studying how muscle injury causes kidney failure in a rat model.
It was known that after skeletal muscle is damaged, it breaks down (lyses) — a condition called rhabdomyolysis — and releases its cellular contents, including myoglobin, into the bloodstream. It was thought that myoglobin deposited in and “plugged up” the kidneys.
“That's not how it works,” Roberts said.
The released myoglobin does deposit in the kidney, but the researchers found that it undergoes “redox cycling” — chemical reactions that generate reactive free radicals, which in turn cause oxidative damage and kidney failure.
Meanwhile, just down the hall from Roberts' lab, Boutaud and John Oates Jr., M.D., professor of Medicine and Pharmacology, were investigating the actions of acetaminophen.
They wanted to understand why the drug was effective against fevers, but not against inflammation — characteristics that made it different from other drugs like aspirin and ibuprofen that act on the same molecular target, a protein called cyclooxygenase (COX).
They discovered that rather than blocking the active site of COX — like aspirin and other anti-inflammatory drugs do — acetaminophen instead blocked a different enzyme activity (a “peroxidase” activity) within the COX protein.
During informal conversations about their studies, members of the two teams realized that the myoglobin redox cycling in the rhabdomyolysis model represented a “pseudo-peroxidase” type of activity that was similar to the COX activity blocked by acetaminophen.
“We said, 'aha, maybe acetaminophen would inhibit the pseudo-peroxidase activity of hemoproteins like myoglobin,'” Roberts said. “And it does.”
The researchers then demonstrated in extensive in vitro studies that acetaminophen blocks the redox cycling of myoglobin and hemoglobin and prevents the oxidation of lipids (fatty molecules that are targets of oxidative damage).
They also showed in the rat model of rhabdomyolysis-induced renal failure that acetaminophen decreased lipid oxidation and reduced the formation of myoglobin crosslinked to other proteins, extremely toxic entities.
“We made a direct connection between the molecular mechanism of acetaminophen in vitro and the actions of the drug in vivo,” Boutaud said.
Acetaminophen administered before or after the skeletal muscle injury in the rat model prevented oxidative injury to the kidneys, improved renal function and reduced renal damage. And importantly, the effective acetaminophen concentrations in the rat matched normal therapeutic concentrations in humans.
Kevin Moore, M.D., Ph.D., and his colleagues at the University College London Medical School conducted the rat model studies.
“The rat rhabdomyolysis model is a proof-of-concept of what we showed in vitro and suggests broad applications of acetaminophen,” Oates said.
The investigators already have a blinded clinical trial under way in collaboration with Robert Mericle, M.D., in the Department of Neurological Surgery testing the effects of acetaminophen in patients with subarachnoid hemorrhage.
In this condition, red blood cells in the cerebrospinal fluid lyse and release hemoglobin, which “does this same redox chemistry,” Roberts said.
Acetaminophen also may prevent tissue damage in other conditions in which oxygen-carrying heme proteins (myoglobin and hemoglobin) are released from cells, including heart attacks, malaria and sickle cell disease.
Roberts points out that soldiers at risk of suffering muscle injuries from gunfire or explosive devices may benefit from acetaminophen as well. “I think every soldier and every medic in the field should have a syringe full of acetaminophen to administer right away to those who suffer muscle injuries,” he said.
But first, controlled studies in humans are needed to confirm that acetaminophen prevents tissue damage and that it's safe. Acetaminophen at high doses is toxic to the liver, so the investigators also are collaborating with Vanderbilt chemist Ned Porter, Ph.D., to synthesize new compounds that are more potent than acetaminophen and that share its mechanism of action, but not its toxicity.
The research was supported by the National Institutes of Health, the Biotechnology and Biological Sciences Research Council (UK), and the Medical Research Council and the Wellcome Trust (UK).
Oates, Boutaud and Roberts have filed a patent for this use of acetaminophen.
Oates is the Thomas F. Frist Sr. Professor of Medicine. Roberts is the T. Edwin Rogers Professor of Pharmacology.©2014 Vanderbilt University Medical Center