ATP-binding cassette (ABC) transporters in normal and pathological lung

Abstract

ATP-binding cassette (ABC) transporters are a family of transmembrane proteins that can transport a wide variety of substrates across biological membranes in an energy-dependent manner. Many ABC transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) are highly expressed in bronchial epithelium. This review aims to give new insights in the possible functions of ABC molecules in the lung in view of their expression in different cell types. Furthermore, their role in protection against noxious compounds, e.g. air pollutants and cigarette smoke components, will be discussed as well as the (mal)function in normal and pathological lung. Several pulmonary drugs are substrates for ABC transporters and therefore, the delivery of these drugs to the site of action may be highly dependent on the presence and activity of many ABC transporters in several cell types. Three ABC transporters are known to play an important role in lung functioning. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene can cause cystic fibrosis, and mutations in ABCA1 and ABCA3 are responsible for respectively Tangier disease and fatal surfactant deficiency. The role of altered function of ABC transporters in highly prevalent pulmonary diseases such as asthma or chronic obstructive pulmonary disease (COPD) have hardly been investigated so far. We especially focused on polymorphisms, knock-out mice models and in vitro results of pulmonary research. Insight in the function of ABC transporters in the lung may open new ways to facilitate treatment of lung diseases.

Genetic susceptibility of lung cancer associated with common variants in the 3′ untranslated regions of the adenosine triphosphate‐binding cassette B1 (ABCB1) and ABCC1 candidate transporter genes for carcinogen export

“…Their dysfunction, which may result in part from polymorphisms in their coding genes, could have implications for the development of lung cancer. 21 The identification of sequence variants of ABCB1 and functional characterization of their biologic significance and clinical relevance with respect to drug disposition has stimulated interest in the pharmacogenetics of xenobiotic phase III transporters. 22 However, the relevance of the results from many previous studies that focused primarily on common single-nucleotide polymorphisms (SNPs) in coding exons remains to be corroborated, because there have been some conflicting results from many population-based association studies.…”

Pharmacogenetics of Asthma

“…This gene is located on chromosome 16p13.12 and demonstrates significant heterogeneity (Saito et al, 2002;van der Deen et al, 2005). One of the polymorphisms of this gene, that was thought to be correlated to drug response, namely rs119774, described by Lima et al was related to a significant FEV1 improvement in subjects receiving montelukast for 6 months (Lima et al, 2006).…”

Pharmacogenomics Dictate Pharmacokinetics: Polymorphisms in Drug-Metabolizing Enzymes and Drug-Transporters

“…in which CYP and ABC transporter expression may regulate drug distribution and clearance. For example, mutations in the ABC transporter, cystic fibrosis transmembrane conductance regulator (CFTR) is responsible for the development of the lung disorder cystic fibrosis, while the cause of Tangier disease, a high cholesterol-related condition, is attributed to mutations in ABCA1 (van der Deen et al, 2005). Other studies provide evidence that genetic polymorphisms exert an effect on interethnic variation and frequency of CYP and multi-drug resistance gene (MDR1) alleles among Orientals, Caucasians and Africans (Iida A, 2002;Lai et al, 2011).…”