Mucosal Expression of the Cytochromes P450 (CYP) and Nucleotide Kinases Involved in the Biotransformation of Drugs Used in Human Immunodeficiency Virus (HIV) Pre‐exposure Prophylaxis (PrEP)

Abstract

Attempts to prevent HIV infection through PrEP have included topical application of anti‐HIV drugs to the mucosal sites of infection. However, clinical studies have revealed marked anatomic variability in drug exposure in vaginal tissue versus colorectal tissue. Thus, studies were performed to determine whether the CYPs and nucleotide kinases responsible for the metabolism and activation of drugs used in HIV PrEP were differentially expressed in human vaginal versus colonic tissue. Quantitative reverse transcriptase‐PCR revealed that colonic mRNA expression of CYPs 1A1, 2B6, and 3A4/5 were 14‐, 37‐ and 4‐fold greater, respectively, than vaginal mRNA. Immunoblotting confirmed the presence of CYPs 3A4 and 3A5 protein in vagina. The vaginal mRNA abundance of adenylate kinase 2, the primary enzyme responsible for the activation of the HIV PrEP drug tenofovir, was 1.5‐fold greater than in colonic tissue. Cytidine monophosphate kinase mRNAs were 8‐fold greater in colonic tissue and phosphoglycerate kinase mRNAs were 4‐fold greater in vaginal tissue. These kinases have been proposed to activate emtricitabine, which is also under development as a topical microbicide for HIV PrEP. These data indicate that enzymes that modulate exposure to anti‐HIV drugs may be differentially expressed in mucosal tissues that are sites of topical drug application for PrEP. Funding: NIH U01 AI068613 (HIV Prevention Trials Network).