More evidence the blood brain barrier is a drug metabolizing system!

 

I've never had a pharmacology class. I started with a book called something like "pharmacology made very very simple for people who are a little slower than average." In that book it is pretty clear that drug metabolism occurs in the liver. You can find similar things by googling "where does drug metabolism occur" like this nice picture from the European Patient's Academy.

So when (now Dr.) Abigail Wheeler hypothesized that toxic effects of HIV antiretroviral drugs were due to drugs being metabolized by cells at the brain and not cells at the liver, she had several tough years to build evidence for that case. She had to quantify metabolism products and use painful targeted quantification to make the case that drug metabolizing enzymes were really present in a lot of places outside the liver.

Fast forward some technology improvements and a couple years of hard work by another young scientist and some helpers and -  here is how and where that drug metabolism (and transport of those drugs and drug metabolites) happens at the blood brain barrier!

Again - this is some controversial stuff - so there are pages and pages of validation including western blots and FACS and efflux assays and other words I don't know. 

For the proteomics stuff, diaPASEF on a TIMSTOF Flex (later model, so Pro2 cartridge) was used to characterize the cells that make up the blood brain barrier. The files were processed in SpectroNaut and the proteomic ruler technique was adapted to generate solid copy number and nM concentration estimates for 8,000 or so proteins. Those numbers are summarized on a nice Shiny web portal which can be directly accessed here. 

Oh yeah, and I didn't do any of this study, I taught author 1 how to do really good proteomics and author 3 how to write stuff in R, kept the service plans paid and tried (unsuccessfully) to keep all the instruments from being destroyed by floods. Boom - Hannah wrote a really nice story that helps illuminate some serious questions we have about drug toxicity and I have a great new resource bookmarked at the top of my browser.