Transport of the β-O-Glucuronide Conjugate of the Tobacco-specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the Multidrug Resistance Protein 1 (MRP1)

The MRP family of drug efflux pumps

“…In addition to uncharged compounds, certain anionic conjugates such as estrone-3 sulfate and the glucuronide conjugate of a nitrosamine metabolite, NNAL-O-glucuronide, are also dependent upon glutathione, and transport of etoposide-glucuronide, which can be measured in the absence of glutathione, is enhanced by the tripeptide (Sakamoto et al, 1999;Leslie et al, 2001;Qian et al, 2001). Interestingly, transport of the former two compounds does not appear to be associated with cotransport of glutathione, and is therefore considered to be the result of a positive allosteric effect by glutathione (Figure 3c).…”

Role of the NH2-terminal Membrane Spanning Domain of Multidrug Resistance Protein 1/ABCC1 in Protein Processing and Trafficking

“…Many potential physiological and exogenous substrates of MRP1 are organic anion conjugates with glutathione (GSH), glucuronate, or sulfate . In addition, the protein is capable of ATP-dependent, GSH-stimulated transport of various unconjugated hydrophobic substrates (Loe et al, , 1997Renes et al, 1999), as well as certain glucuronate and sulfate conjugates (Sakamoto et al, 1999;Leslie et al, 2001;Qian et al, 2001b).…”

“…Many potential physiological and exogenous substrates of MRP1 are organic anion conjugates with glutathione (GSH), glucuronate, or sulfate . In addition, the protein is capable of ATP-dependent, GSH-stimulated transport of various unconjugated hydrophobic substrates (Loe et al, , 1997Renes et al, 1999), as well as certain glucuronate and sulfate conjugates (Sakamoto et al, 1999;Leslie et al, 2001;Qian et al, 2001b).ABC proteins typically consist of two tandemly arranged polytopic membrane spanning domains (MSDs) and two cytoplasmic nucleotide binding domains (NBDs) (Higgins, 2001). In addition to the four "core" domains, MRP1 and certain other ABCC proteins contain a third, NH 2 -terminal MSD (MSD0) .…”

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

“…7 And the conjugated metabolites, such as NNALGluc, finally are transported and eliminated by the phase III adenosine-5 0 -tripohsphate-binding cassette transporters, such as adenosine triphosphate-binding cassette B1 (ABCC1). 8,9 It has been well documented that difference in genetic susceptibility to lung cancer among individuals is caused in part by their varied capacity for metabolism and the disposition of xenobiotics, such as the tobacco-specific carcinogen NNK. For example, we and other groups have documented that the interaction of CYP2A13 and NNK is associated with lung cancer.…”

“…16,17 It has been demonstrated clearly that ABCC1 mediates the transport and elimination of metabolites of the tobacco-specific carcinogen NNK. 8 The transport substrates of ABCB1 include environmental carcinogens that are present in cigarette smoke or diet, such as benzo(a)-pyrene, 18 7,12-dimethylbenzanthracene, 19 or 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine. 20 The 2 ABC transporters are supposed to be the most important transporters in normal lung physiology protecting the lungs against inhaled toxicants.…”