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Part-IIIAdvances Dihydropyridines and …Figure-4. Multi-drug transporters in the human liver hepatocytes. Abbreviations: TJ, tightjunction. (Reproduced from reference- 4)1.4.5 Molecular Mechanism of the Multidrug PumpsDrug transport by MDR proteins requires the energy of ATP-hydrolysis, controlled bydrug interaction, and closely coupled to the actual drug translocation. Interaction with thedrug-substrate significantly enhances the basal ATPase activity of the multidrugtransporters, that is, the transported drug-substrates increase the rate of ATP cleavage. 51-53The schematic pictures of the proposed molecular mechanisms of the MDR1 and MRP1proteins, as depicted in Figure-5.The site(s) in multidrug transporters interacting with the drug-substrates are probablyencoded in the transmembrane domains. Detailed mutagenesis studies of MDR1 andphotochemical labeling with the reactive drug-derivatives revealed that transmembranehelices 5 and 6 (in the N-proximal transmembrane domain), helices 11 and 12 (in the C-proximal transmembrane domain), as well as the short cytoplasmic loops connectingthese helices, are involved in the formation of an extended drug-binding site(s). 54 Thereare strong indications that the hydrophobic substrates of MDR1 are recognized within themembrane bilayer or in its vicinity, and this type of recognition makes the MDR1 proteina highly effective pump, preventing the cellular entry of toxic compounds. 55 In the case ofMRP1 a similar picture has emerged. Recent studies have explored some parts of thetransmembrane domains involved in drug interactions. 56396