BCRP (encoded by the ABCG2 gene), an efflux transporter in the ATP binding cassette (ABC) superfamily, is located on epithelial cells of the kidney, liver, and intestine as well as on the endothelial cells of the blood-brain barrier. Recent studies have implicated a reduced function variant in ABCG2, which encodes an amino acid change from glutamine to lysine at position 141 of the protein (rs2231142), as a determinant of the pharmacokinetics, response, and toxicity of several drugs. The variant has a low frequency in individuals of African ancestry but is found at an allele frequency of about 30% in East Asians including Chinese and Japanese. Notably, the variant has been associated with changes in response to the xanthine oxidase inhibitor, allopurinol, and the statin rosuvastatin. In addition, the variant has been associated with toxicity to various anticancer drugs. Because of its high allele frequency, particularly in Asian populations, and the fact that the transporter is a determinant of the pharmacokinetics of many drugs, it is likely that this variant will become increasingly important in precision medicine.
Genetic predispositions to drug response and toxicities are not limited to genes related to pharmacokinetic processes, eg, drug-metabolizing enzymes and drug transporters. Additional genetic sources of variation may include genes involved in pharmacodynamic processes such as drug receptors and drug targets.
For example, a polymorphism in HLA loci is associated with a predisposition to drug toxicity.
Hypersensitivity reactions to various drugs can range from mild rashes to severe skin toxicities. The most severe hypersensitivity reactions are liver injury, toxic epidermal necrosis (TEN), and Stevens-Johnson syndrome (SJS), in which drugs or their metabolites form antigens. Drug classes associated with hypersensitivity reactions include sulfonamides, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, steroids, anti-epileptic agents, and methotrexate.
Hypersensitivity reactions have varying prevalence rates in different racial and ethnic populations. For example, carbamazepineinduced skin toxicities have an increased prevalence in East Asian populations. Population-based hypersensitivity reactions have been attributed to genetic polymorphisms in the HLA system, which are part of the major histocompatibility complex (MHC) gene family (see also Chapter 55). Of the several HLA forms, HLA-B, HLA-DQ, and HLA-DR polymorphisms have been associated with many drug-induced hypersensitivity reactions, including reactions to allopurinol, carbamazepine, abacavir, and flucloxacillin (Table 5–4).
Many HLA-B polymorphisms have been characterized and have varying allele frequencies depending on the racial and ethnic population. A polymorphism in HLA-B may result in altered antigen-binding sites in the HLA molecule, which in turn may recognize different peptides. The selective recognition of particular drug-bound peptides by some HLA-B polymorphism products results in population-selective drug hypersensitivity reactions.
Example 1: Abacavir, a nucleoside reverse transcriptase inhibitor used in the treatment of HIV, is associated with hypersensitivity reactions in the skin, particularly SJS, which for with Stevens-Johnson syndrome, toxic epidermal necrosis, or drug-induced liver injury.
ALT, alanine transaminase.
many years appeared to be idiosyncratic, ie, of unknown mecha-