Identification of Alverine and Benfluorex as HNF4α Activators

The
principal finding of this study is that two drugs, alverine
and benfluorex, used in vastly different clinical settings, activated
the nuclear receptor transcription factor HNF4α. Both were hits
in a high-throughput screen for compounds that reversed the inhibitory
effect of the fatty acid palmitate on human insulin promoter activity.
Alverine is used in the treatment of irritable bowel syndrome, while
benfluorex (Mediator) was used to treat hyperlipidemia and type II
diabetes. Benfluorex was withdrawn from the market recently because
of serious cardiovascular side effects related to fenfluramine-like
activity. Strikingly, alverine and benfluorex have a previously unrecognized
structural similarity, consistent with a common mechanism of action.
Gene expression and biochemical studies revealed that they both activate
HNF4α. This novel mechanism of action should lead to a reinterpretation
of previous studies with these drugs and suggests a path toward the
development of therapies for diseases such as inflammatory bowel and
diabetes that may respond to HNF4α activators.