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Grant Abstract: Genetic Variants Associated with Tacrolimus Metabolism in Kidney Transplant Recipients

Grant Number: 5K01AI130409-02
PI Name: Dorr
Project Title: Genetic Variants Associated with Tacrolimus Metabolism in Kidney Transplant Recipients

Abstract: The dietary supplement St. John’s Wort (SJW) (Hypericum perforatum), used as an antidepressant, affects drugs such as Tacrolimus (TAC) and Midazolam (MDZ) that are metabolized by CYP3A4 and CYP3A5 (CYP3A4/5). However, the role of the CYP3A4/5 genotype in these interactions is unknown. CYP3A5 and its homolog CYP3A4, together, metabolize ~50% of all prescribed drugs in the United States including MDZ and TAC. TAC is an immune suppressant used in 90% of solid organ transplants and MDZ is a common sedative. SJW has shown to increase Tac and MDZ metabolism. There are differences in Tac metabolism in African Americans (AA) and European Americans (EA) partially based on CYP3A5 genotype. It is likely that genotype and SJW are clinical factors that need to be accounted for in the medical dosing of CYP3A4/5 metabolized drugs. We will determine how CYP3A5 genotypes affect the metabolism of the drugs that interact with SJW. The central hypothesis is that the CYP3A5 genotype will impact the interactions of dietary supplements and TAC and MDZ metabolism via the CYP3A4 and CYP3A5 pathway. The CYP3A5*1 genotype is common in AAs and leads to active CYP3A5. The *3 (rs776756) genotype is common in EAs and leads to inactive CYP3A5. The CYP3A5*6 (rs10264272) genotype is common in AAs reduces CYP3A5 activity. With limited studies in AAs there is minimal understanding of the interactions of SJW with CYP3A5 *1 or *6 genotypes. Thus, we propose to determine the differences that the CYP3A5 *1 or *3 (Aim1) and that the CYP3A5 *1 or *6 genotypes (Aim 2) play in TAC or MDZ metabolism in the presence of SJW. We will conduct cell culture experiments with our previously published methods. We will treat CRISPR modified CYP3A5 *1 or *3 human liver cell lines with Tac or MDZ in the presence of SJW extract and measure the effect CYP3A5 genotype has on Tac and MDZ metabolism separately (Aim1). We will repeat this with the SJW active component hyperforin that has been shown to increase CYP3A4/5activity via activation of the transcription factor Pregnane X Receptor (PXR). Since hyperforin activates PXR, which activates CYP3A4/5, we hypothesize CYP3A5*1 genotype will lead to increased metabolism compared with CYP3A5*3. In Aim 2, we will bioengineer a new cell line with genotype CYP3A5*6 and determine the effects SJW extract and hyperforin have on MDZ and TAC metabolism. To achieve clinically relevant compound/extract concentrations, we will conduct cell toxicity assays with SJW and hyperforin and dose response curves with MDZ and TAC using SJW or hyperforin as titrated chemicals. We will characterize the new CYP3A5*6 cell lines by RT-PCR and immunoblot. We will use RNA sequencing and Ingenuity Pathway Analysis to elucidate the extracts’ and compounds’ mechanisms of action. This supplement will expand on Dr. Dorr’s K01 study “Genetic Variants Associated with Tacrolimus Metabolism in Kidney Transplant Recipients” by determining the role genetics play in the interaction of dietary supplements with drug metabolism which may lead to safer dosing guidelines.

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