last updated April 2013
Clearing sedatives from the bloodstream
Enhanced metabolism of the sedative flunitrazepam by a mutant bacterial enzyme accelerates recovery in sedated mice
Sedatives used to combat insomnia and anxiety can become dangerous suppressors of neurological function. For example, an overdose of nitrobenzodiazepines, such as the widely used flunitrazepam, can cause hallucinations, seizures and death; long-term use leads to addiction. Such sedatives are also misused as date rape drugs; flunitrazepam is more commonly known as Rohypnol. The current antidote to flunitrazepam simply blocks its action, leaving the body to metabolize it, which can generate toxic products. A therapy to clear the drug from the bloodstream may now be possible, thanks to recent work led by Andrew Wang at Academia Sinica, Taiwain1.
The bacterial enzyme NfsB metabolizes flunitrazepam to a single non-toxic product. Normally, NfsB works better in oxygen-free conditions than in the aerobic environment of the human body. Wang and his team, however, mutated the enzyme’s active site to boost its activity in the presence of oxygen. Crystal structures revealed that a pocket in the active site was enlarged by the mutation.
“This may prevent the reversion of the reaction intermediates efficiently under aerobic conditions and improve the catalytic activity,” explains co-author Shiuan-Woei LinWu.
In flunitrazepam-sedated mice, the mutant enzyme cleared the drug from the bloodstream and reversed sedation more effectively than the wild-type, proving its potential for future therapy in humans.