Gene Number: 10599

Location: 12p12.1

Key Functions: Hepatic drug transport, statin metabolism, bilirubin clearance

The SLCO1B1 gene, located on chromosome 12p12.1, encodes the organic anion transporting polypeptide 1B1 (OATP1B1), a key hepatic membrane transporter responsible for shuttling diverse endogenous molecules and xenobiotics from the bloodstream into hepatocytes. Functionally, OATP1B1 acts as a gatekeeper for hepatic drug clearance, mediating the uptake of statins, bilirubin, bile acids, hormones, and therapeutic agents such as methotrexate and repaglinide.

At the molecular level, OATP1B1 is expressed on the basolateral (sinusoidal) membrane of liver cells, where it functions as part of a coordinated network of hepatic transporters that maintain metabolic homeostasis. Its most clinically relevant role is in statin pharmacokinetics—particularly the hepatic uptake of simvastatin, atorvastatin, and pravastatin. Reduced transporter function limits statin delivery to the liver, where cholesterol synthesis occurs, and instead increases systemic statin exposure in muscle tissue, predisposing susceptible individuals to statin-induced myopathy.

From a genetic standpoint, several SLCO1B1 polymorphisms have well-established pharmacogenomic significance. The most prominent variant, rs4149056 (c.521T>C; p.Val174Ala), results in diminished transporter activity due to altered protein folding and reduced membrane localization. Carriers of the C allele—especially homozygotes (CC)—display up to a 200–400% increase in plasma statin concentrations, drastically elevating myopathy risk. This variant defines the SLCO1B1*5 haplotype, which has become a clinical biomarker in personalized statin therapy.

Beyond its pharmacogenetic impact, SLCO1B1 plays a vital role in bilirubin clearance by mediating hepatic uptake of unconjugated bilirubin. Dysfunctional SLCO1B1 variants can contribute to mild hyperbilirubinemia, often overlapping with phenotypes of Gilbert’s syndrome, when combined with UGT1A1 polymorphisms. Additionally, OATP1B1 modulates systemic exposure to several chemotherapeutic and antidiabetic agents, influencing both efficacy and toxicity profiles.

Clinically, SLCO1B1 genotyping is now incorporated into pharmacogenomic testing panels for statin therapy optimization. Understanding a patient’s SLCO1B1 genotype allows for dose adjustment or drug substitution—for example, using rosuvastatin or fluvastatin, which rely less on OATP1B1-mediated transport.

In summary, SLCO1B1 represents a central genetic determinant in hepatic drug transport and personalized pharmacotherapy. By bridging molecular transport biology with clinical pharmacogenomics, it underscores how subtle genetic variation can define the line between therapeutic success and adverse drug reactions.