Limited modulation of the transport activity of the human multidrug resistance proteins MRP1, MRP2 and MRP3 by nicotine glucuronide metabolites.
The human ATP-binding cassette proteins MRP1 (ABCC1), MRP2 (ABCC2) and MRP3 (ABCC3) are active transporters of antineoplastic drugs as well as conjugated metabolites and other organic anions. In addition to being substrates, many glucuronide, glutathione and sulfate conjugates can also inhibit the transport activities of these MRP-related proteins, sometimes in a glutathione (GSH)-dependent manner. Nicotine is the major addictive component of cigarette smoke. Three glucuronide metabolites of this compound have been identified in vivo: nicotine-N-glucuronide, cotinine-N-glucuronide and trans-hydroxycotinine-O-glucuronide. In this study, we first chemically synthesized trans-hydroxycotinine-O-glucuronide and then tested the ability of this compound, nicotine-N-glucuronide and cotinine-N-glucuronide to modulate the vesicular transport of several organic anions by MRP1, MRP2 and MRP3. We observed that none of the three metabolites at concentrations up to 100muM significantly affected organic anion transport by MRP1 or MRP2, either in the absence or presence of GSH. MRP3-mediated transport of 17beta-estradiol 17-(beta-d-glucuronide) and methotrexate were partially inhibited by trans-hydroxycotinine-O-glucuronide (300 microM) (by 70% and 50%, respectively), whereas nicotine-N-glucuronide and cotinine-N-glucuronide had no effect. We conclude that the physiological functions of MRP1, MRP2 and MRP3 are not likely to be substantially affected by nicotine glucuronide metabolites at concentrations achievable in human serum.
Létourneau
Isabelle J
IJ
Department of Pharmacology and Toxicology, Queen's University, Botterell Hall, Stuart Street, Kingston, Ont., Canada K7L 3N6.
Bowers
Raymond J
RJ
Deeley
Roger G
RG
Cole
Susan P C
SP
D018528:ATP-Binding Cassette Transporters; D018929:Cell Culture Techniques; D018432:Drug Resistance, Multiple; D005731:Ganglionic Stimulants / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D017136:Ion Transport; D007668:Kidney / Q000166:cytology; D026901:Membrane Transport Proteins / Q000494:pharmacology*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000494:pharmacology*; D009538:Nicotine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D011726:Pyridinium Compounds; D012907:Smoking
D018528:ATP-Binding Cassette Transporters; D005731:Ganglionic Stimulants; D005965:Glucuronates; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009538:Nicotine; D011726:Pyridinium Compounds; C000715087:ABCC2 protein, human; C085795:nicotine N-glucuronide; C114462:multidrug resistance-associated protein 3; C421109:multidrug resistance-associated protein 1