Changes in Protein Expression of Renal Drug Transporters and Drug‐Metabolizing Enzymes in Autosomal Dominant Polycystic Kidney Disease Patients

TL;DR

This study examines how proteins involved in drug metabolism and transport change in patients with autosomal dominant polycystic kidney disease at different stages.

Contribution

The paper provides new proteomic data on drug-metabolizing enzymes and transporters in early and end-stage ADPKD patients.

Findings

Early-stage ADPKD showed minimal changes in drug transporter and enzyme proteins compared to healthy controls.

End-stage ADPKD exhibited significant reductions in several drug-metabolizing enzymes and undetectable levels of key transporters.

MDR1 was the only efflux transporter consistently measurable in end-stage ADPKD samples.

Abstract

Autosomal dominant polycystic kidney disease is the most prevalent inherited kidney disease and leads to bilateral kidney enlargement and progressive loss of renal function, often over decades. Comorbidities include hypertension, flank pain, and bacterial infections. The condition often necessitates prolonged multidrug therapy. Given the kidneys' critical role in drug excretion, the progressive functional impairment in the disease can lead to complications such as drug overdosing and unexpected levels of drug–drug interactions. Studies of drug‐metabolizing enzyme and transporter expression in this patient group remain scarce. We conducted comprehensive global liquid chromatography–tandem mass spectrometry proteomic analyses of microsomal and cytosolic fractions from early‐stage (chronic kidney disease stage: 13, n = 16) and end‐stage autosomal dominant polycystic kidney disease patients (chronic kidney disease stage: 5, n = 14), comparing them with age‐matched healthy controls (n = 11). In the early‐stage ADPKD samples, most drug‐metabolizing enzymes and drug transporters did not differ significantly from the healthy controls. Exceptions were EPHX2 and SULT1C2 in the cytosolic fraction, which showed a more than 2‐fold decrease in abundance (P < 0.05). In contrast, the end‐stage ADPKD kidney samples showed a decrease in the abundance of most measured proteins. Several drug‐metabolizing enzymes, including CYP4F2, UGT1A6, UGT1A9, and UGT2B7, exhibited statistically significant reductions (P < 0.05). Among the drug transporters, OAT1, OAT3, and OCT2 were below the limit of quantification in most ES‐ADPKD samples. MDR1 was the only efflux drug transporter consistently measured, with an average abundance of 1.24 pmol/mg microsomal protein across all samples.

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