Extra-hepatic CYP3A5 expression in tissue defence against toxicity

Overview

Many toxins and active drugs are filtered out of the bloodstream and into urine by the kidneys. The concentrating effect of the kidneys means the bladder lining (“urothelium”) is exposed to high doses of chemicals/drugs for much longer than the rest of the body. We are interested in how the urothelium copes with exposure to these toxins and have good preliminary evidence that the tissue makes enzymes, known as cytochrome P450s (CYPs), which can break down drugs and chemicals. This is a new idea, as most drug-metabolising activity is attributed to the liver and we believe our discovery opens the doors to understanding bladder disease and helping the design of bladder therapies. Importantly, we are able to demonstrate this CYP-activity using human urothelium recreated by growing cells in the laboratory which allows us to perform experiments that used to be done using rats.

This project will look at a specific enzyme, known as CYP3A5, which is present in the urothelium. We will run experiments to demonstrate that CYP3A5 is required for urothelium to metabolise specific drugs and we will also study tissues from patients to see if loss/gain of CYP3A5 is associated with bladder disease.