Multidrug resistance related molecules in human and murine lung

Abstract

Aims: Transporter proteins known to mediate multidrug resistance (MDR) in tumour cells-MDR1 P-glycoprotein (P-gp) and multidrug resistance related protein 1 (MRP1)-are thought to be involved in protecting the lungs against inhaled toxic pollutants. Recently, several new transporter family members have been identified-for example, MRP2, MRP3, and breast cancer resistance protein (BCRP). To study the possible contribution of these proteins and the earlier defined MDR1 and MDR3 P-gp molecules, MRP1, and the major vault protein (MVP) to lung functioning, their expression was analysed in normal lung tissue of humans and several animal species. Methods: Frozen sections of normal lung tissues were examined for the expression of the multidrug resistance associated proteins, using an extended panel of monoclonal antibodies that specifically detect these proteins in immunohistochemical techniques. Results: In line with earlier reports, the expression of MDR1 P-gp and MRP1 was readily detected in the apical and basolateral membranes, respectively, of the epithelial cell layers of the lungs. In addition, prominent cytoplasmic MVP staining was detected in these layers. In contrast, the recently discovered transporters were either undetectable or they were present at very low values in lung tissue. Immunohistochemical staining in tissues from mice, rats, and guinea pigs points to a strong evolutionary conservation for these transporter proteins. Conclusions: These results show that the "classic" MDR related molecules, MDR1 P-gp, MRP1, and MVP, should be considered the most important transporters in normal lung physiology. It will be of great interest to investigate differences in expression of both classic and newly defined transporters between normal individuals and-for example, patients with various bronchopulmonary pathological conditions.

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

“…9 ABCB1 lies on the apical surface of bronchial and bronchiolar epithelium and functions to remove toxicants to the lung lumen. 15 ABCC1 is located with relatively high expression on the basolateral surface of the epithelia layer, and it can transport toxins into the lung interstitial space. 15 This case-control association study, together with the biochemical observation that the metabolites of tobacco-specific NNK are transported and eliminated by ABC transporters such as ABCC1, highlights the possibility that they also may influence individual susceptibility to lung cancer.…”

“…15 ABCC1 is located with relatively high expression on the basolateral surface of the epithelia layer, and it can transport toxins into the lung interstitial space. 15 This case-control association study, together with the biochemical observation that the metabolites of tobacco-specific NNK are transported and eliminated by ABC transporters such as ABCC1, highlights the possibility that they also may influence individual susceptibility to lung cancer. The common variants of ABCB1 rs3842 and ABCC1 rs212090 that are associated with the risk of lung cancer are located at the 3 0 UTR, and they are not in linkage disequilibrium with other potentially functional SNPs in the Chinese population.…”

“…ABCB1, also known as multidrug resistance 1 (MDR1) or P-glycoprotein (P-gp), and ABCC1, also known as multidrug resistance protein 1 (MRP1), are expressed at relatively high levels in both normal 15 and cancerous lung tissue. 16,17 It has been demonstrated clearly that ABCC1 mediates the transport and elimination of metabolites of the tobacco-specific carcinogen NNK.…”

Harnessing drug resistance: Using ABC transporter proteins to target cancer cells

“…Such tissues include the liver, intestines and kidney [19][20][21][22][23][24][25][26][27][28][29]. In general, the major routes of xenobiotic excretion are through urine and feces, although the lung can also expel xenobiotics via exhalation.…”

“…In the 23 tissues profiled, MRP4 is highly expressed in 3, moderately expressed in 5, expressed low in 12, and shows very low to no expression in 3 tissues. In addition, this MRP tissue expression is variable among species [19].…”