Structural and functional implications of ABCC1 variants on clinical statin response

ATP-binding cassette (ABC) proteins are membrane transporters responsible for metabolites and active substances removal from cells. Their genes’ variations have been associated with protein function and expression defects. Familial Hypercholesterolemia (FH) patients hosting those alterations might compromise the efficacy of high-dose statin treatment, a primary therapeutic strategy. <i>ABCC1</i> is a member of the ABC-transporter superfamily, potentially relevant to pharmacological therapy responses and toxicity risks in hypercholesterolemic patients. Here, we evaluated specific non-synonymous (SNV) missense variants in the <i>ABCC1</i> gene from a FH patient cohort, assessing potential impacts on protein structure, molecular dynamics and interactions with rosuvastatin, atorvastatin, pravastatin, pitavastatin, and lovastatin. Molecular docking, complemented by motion, visual and binding affinity analysis using the PLANNET model, suggested that these mutations had minimal impact on drug interactions. These findings prompted further analysis of two other efflux pumps, <i>ABCG2</i> and <i>P-gp</i>, and their statin interactions. Interestingly, diminished binding affinities hinted at a compensatory mechanism wherein other transporters might mitigate potential <i>ABCC1</i> mutation effects, ensuring effective drug efflux. Clinical profiles from the patient cohort did not show a correlation between these variants and clinical outcomes, potentially pointing to the role of alternate drug transporters in statin interaction. Diagram depicting the compensatory turnover of alternate transporters in response to statins’ preferential binding to ABCC1, and its impact on the clinical outcomes for patients with familial hypercholesterolemia. It represents how <i>ABCG2</i> (pink) and <i>P-gp</i> (orange) are more capable of depleting statins from the intracellular ambient than ABCC1 (purple), thus impacting statin treatment.