ABSTRACT
Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (ß = 2.16, P = 0.024; ß = 1.92, P = 0.016; odds ratio 95% CI = 2.29-∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.
Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Chemical and Drug Induced Liver Injury/etiology , Endothelin Receptor Antagonists , Hypertension, Pulmonary/drug therapy , Sulfonamides/adverse effects , Alanine Transaminase/metabolism , Aryl Hydrocarbon Hydroxylases/metabolism , Aspartate Aminotransferases/metabolism , Bosentan , Chemical and Drug Induced Liver Injury/enzymology , Cytochrome P-450 CYP2C9 , Female , Genetic Association Studies , Genetic Markers , HEK293 Cells , Humans , Liver-Specific Organic Anion Transporter 1 , Male , Middle Aged , Multidrug Resistance-Associated Protein 2 , Organic Anion Transporters/genetics , Polymorphism, Single NucleotideABSTRACT
Reports of high-grade non-Hodgkin's lymphoma, Hodgkin's disease, and lymphocytic leukemia in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-like immune disorders have been increasing. In some cases, histologic alterations of lymph node architecture may precede the development of malignant lesions. Early in the course of the disease, clinical profiles of these patients are indistinguishable from those of patients with AIDS-associated opportunistic infections, but rapidly evolving extranodal lesions often signify the establishment of a lymphoproliferative neoplastic process. The frequent involvement of the central nervous system is responsible for the dismal outcome of the disease in a significant number of patients. A high death rate and poor response to antineoplastic agents have often characterized the course of non-Hodgkin's lymphoma and leukemia, but some patients with Hodgkin's disease have had a favorable response to treatment and a long survival. Aggressive multidisciplinary treatment may effectively avert the devastating consequences of this array of lymphoreticular neoplasms. Studies of these intriguing disorders may provide a better understanding of the interrelationships of infection, immunity, and oncogenesis in man.
