NEW
BRUNSWICK, N.J. – Rutgers University and Massachusetts General Hospital (MGH) investigators have developed a novel strategy
to protect the liver from drug-induced injury and improve associated drug
safety.

In a
report receiving advance online publication in the journal Nature Biotechnology, the team reports that inhibiting a type of
cell-to-cell communication can protect against damage caused by liver-toxic
drugs such as acetaminophen.

“Our
findings suggest that this therapy could be a clinically viable strategy for
treating patients with drug-induced liver injury,” said Suraj Patel a
postdoctoral researcher in the Center for Engineering in Medicine at MGH and the
paper’s lead author. “This work also has the potential to change the way drugs
are developed and formulated, which could improve drug safety by providing
medications with reduced risk of liver toxicity.”

Mouselivers exhibit damage after being subjected to the toxins thioacetamide (TAA),upper left, and acetaminophen (APAP), lower left. When these toxins wereadministered with the gap junction inhibitor 2-aminoethoxydipenyl-borate(2APB), upper and lower right, less damage is visible.

Drug-induced
liver injury is the most common cause of acute liver failure in the U.S. and is
also the most frequent reason for abandoning drugs early in development or withdrawing
them from the market. Liver toxicity limits the development of many therapeutic
compounds and presents major challenges to both clinical medicine and to the
pharmaceutical industry.

Since no
pharmaceutical strategies currently exist for preventing drug-induced liver
injury, treatment options are limited to discontinuing the offending drug,
supportive care and transplantation for end-stage liver failure.

 The
researchers investigated an approach that targets a liver’s gap junctions – hollow
multimolecular channels that connect neighboring cells and allow direct
communication between coupled cells. In the heart, gap junctions propagate the
electrical activity required for synchronized contraction, but their role in
the liver has not been well understood

Recent
work has shown that gap junctions spread immune signals from injured liver
cells to surrounding undamaged cells, amplifying inflammation and injury. The
current study examined inhibiting the action of liver-specific gap junctions to
limit drug-induced liver injury.

The
researchers first used a strain of genetically mutated mice that lack a
particular liver-specific gap junction. The mice were administered various
liver-toxic drugs such as acetaminophen, a commonly used medication best known
under the Tylenol brand name. Acetaminophen overdoses are the most frequent
cause of drug-induced liver injury.

Compared
to normal mice, those lacking liver gap junctions were fully protected against
liver damage, inflammation and death caused by administration of liver-toxic
drugs. The team then identified a small-molecule inhibitor of liver gap
junctions that, when given with or even after the toxic drugs, protected the
livers of normal mice against injury and prevented their death.

“This
finding is very exciting and potentially very powerful from a number of basic
science and clinical application standpoints, which we are continuing to
explore,” said Martin Yarmush, senior author of the report and the Paul and
Mary Monroe Professor of Biomedical Engineering at Rutgers. “However, before we
can think about applying this approach to patients, we need to know more about
any off-target effects of gap junction inhibitors and better understand the
long-term ramifications of temporarily blocking liver-specific gap junction
channels.”

Additionally,
cell culture experiments indicated that blocking gap junctions limited the
spread through liver cells of damaging free radicals and oxidative stress,
suggesting a possible mechanism for the observed protection.     

Other co-authors
of the study are Jack Milwid, Kevin King, Stefan Bohr, Arvin Iracheta-Vellve,
Matthew Li, Antonia Vitalo and Biju Parekkadan of MGH, and Rohit Jindal of
Rutgers. The work was supported by grants from the National Institutes of
Health and Shriners Hospitals for Children.