The researchers then added the drug to isolated mitochondria, which is the main site of respiration within the cells.
"But we did not see an effect, so that gave us the idea that this drug may not be directly targeting one of the enzymes of mitochondria which are required for or participates in consuming oxygen," Gohil said. "We used that clue to figure out how non-mitochondrial pathways could be targeted by this drug."
He used an unbiased metabolic profiling approach, a new technology that gives a snapshot of metabolite levels before and after the treatment of a drug so researchers can get an idea of how this drug is perturbing these metabolites.
"Through metabolic profiling, we found one particular metabolite - phosphoethanolamine - was in fact 'going through the roof' within a few hours of the treatment," Gohil said. "We got excited about that."
He explained that phosphoethanolamine is an intermediate in a biosynthetic pathway of a common phospholipid that forms the membrane around the cells. It is present in all living matter from the lower organisms such as bacteria all the way to humans. Thus, finding that the metabolite that was elevated when cells were treated with meclizine indicated a link between this pathway, or metabolite, and respiration.
"Our research showed that if we just take this metabolite and directly add it to mitochondria, it actually inhibits the respiration," Gohil said. "The reason we could use the drug for infectious disease or cancer is not because it inhibits respiration but because it inhibits a phospholipid biosynthetic enzyme that is required to form the building blocks of membranes."
|Contact: Kathleen Phillips|
Texas A&M AgriLife Communications