The SLCO1B1 gene is central to pharmacogenomics, playing a significant part in the body’s ability to process and eliminate many commonly prescribed drugs. Understanding its function is important for personalizing medicine, particularly for patients taking drugs with a narrow therapeutic window. Common variations in this gene can dramatically alter how the body handles certain medicines, directly influencing both their effectiveness and safety. These genetic differences provide a powerful tool for doctors to make more informed treatment decisions.
Defining the Gene and Its Product
The acronym SLCO1B1 stands for Solute Carrier Organic Anion Transporter Family Member 1B1, and this gene contains the instructions for making a protein known as OATP1B1. This protein is a specialized influx transporter, meaning its primary job is to move substances from the outside of a cell to the inside. The OATP1B1 protein is located almost exclusively on the basolateral membrane of liver cells, which is the side facing the bloodstream.
It functions as a selective “in-gate,” actively ferrying various compounds from the circulating blood into the liver for processing and eventual removal from the body. These transported compounds include naturally occurring substances like bilirubin, which is a yellowish byproduct of red blood cell breakdown. The liver uses OATP1B1 to take up bilirubin so it can be dissolved in bile and ultimately excreted.
The OATP1B1 transporter also moves many pharmaceutical drugs from the bloodstream into the liver. This transport step is necessary for the liver to either activate the drug or break it down for elimination. Without sufficient OATP1B1 activity, these drugs remain in the plasma, or bloodstream, for longer periods.
Genetic Variations and Activity Levels
The SLCO1B1 gene exhibits common genetic variations, known as single nucleotide polymorphisms (SNPs), that affect the function of the resulting OATP1B1 protein. These variations lead to changes in the protein’s structure or quantity. The combination of specific SNPs forms different versions of the gene, which are known as haplotypes or star alleles (e.g., \(1A, 1B, 5, 15\)).
An individual inherits two copies of the SLCO1B1 gene, one from each parent, and the combination of these two copies determines their overall OATP1B1 transport capability. The \(1A\) and \(1B\) haplotypes generally result in normal or fully functional OATP1B1 transporters. In contrast, other common haplotypes, such as \(5\) and \(15\), are associated with altered function.
For instance, the \(5\) allele involves a change (rs4149056) that replaces the amino acid valine with alanine in the OATP1B1 protein. This structural change reduces the protein’s ability to transport compounds into the liver, classifying the allele as having decreased or no function. The \(15\) allele combines this reduced function change with another variation (rs2306283), often resulting in a severe reduction or complete loss of transporter activity.
When a person carries one or two copies of these reduced or non-functional alleles, the physical ability of their liver cells to take up drug compounds is impaired. This reduction in transport capability directly translates to a lower rate of drug clearance from the bloodstream, which is why genetic differences in SLCO1B1 lead to distinct drug responses.
Direct Impact on Drug Metabolism
The alteration in OATP1B1 activity caused by SLCO1B1 variations has direct clinical consequences for the metabolism of numerous medications. When the transporter is less effective, affected drugs are not efficiently cleared from the blood and processed by the liver, resulting in higher and more prolonged concentrations circulating in the plasma.
This effect is most extensively studied and understood with the statin class of cholesterol-lowering medications. Statins, such as simvastatin, are substrates for the OATP1B1 transporter, meaning they rely on it to enter the liver where they exert their cholesterol-reducing action. If the transporter is working slowly, the statin stays in the bloodstream and muscle tissue for too long.
The elevated plasma levels of statins increase the risk of serious side effects, most notably myopathy, which is characterized by muscle pain and weakness. In rare but severe cases, this can progress to rhabdomyolysis, a potentially life-threatening condition involving the rapid breakdown of muscle tissue. Carriers of the reduced function \(5\) or \(15\) alleles who are taking high doses of simvastatin, for example, have a substantially increased risk of developing myopathy.
The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that patients with one or two copies of these reduced function alleles should either be prescribed a lower dose of simvastatin or be switched to an alternative statin that is less dependent on OATP1B1, such as pravastatin or rosuvastatin. For simvastatin, the presence of the rs4149056 C allele (part of the \(5\) and \(15\) haplotypes) can increase the risk of myopathy by as much as 4.5 times when taking the highest dose. Genotyping for this specific variation is used clinically to guide dosing and select safer alternatives.
The impact of SLCO1B1 extends beyond statins to other medication classes. The gene’s transporter affects the pharmacokinetics of the chemotherapy agent methotrexate, where variations can alter how quickly the drug is cleared, potentially affecting its efficacy and toxicity. Other affected drugs include certain antivirals, such as some protease inhibitors, and the antibiotic rifampin. Genetic variations in SLCO1B1 are a major consideration in determining personalized treatment plans because the OATP1B1 transporter is involved in the uptake of many different compounds.