Carcinogenesis Advance Access published online on August 27, 2007
Carcinogenesis, doi:10.1093/carcin/bgm187
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Biotransformation and transport of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in bile duct-cannulated wild-type and Mrp2/Abcc2-deficient (TR-) Wistar rats
School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA
Address all correspondence and requests for reprints to: Dr. Kim L.R. Brouwer, CB#7360, Kerr Hall, Rm 2311, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7360 Email: kbrouwer{at}unc.edu; Tel: (919) 966-7030; Fax: (919) 966-0197
The role of uptake and efflux transport proteins in the tissue distribution of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolites is largely unknown. Carbonyl reduction of NNK results in formation of the carcinogenic 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which in rats is glucuronidated to the non-toxic NNAL-O-glucuronide. Previous in vitro studies showed that NNAL-O-glucuronide is a substrate for the human ATP-binding cassette transport proteins MRP1 (ABCC1) and MRP2 (ABCC2). To investigate the influence of Mrp2 deficiency on NNK biotransformation and biliary excretion, [3H]NNK was administered intravenously to bile duct-cannulated wild-type (WT) and Mrp2-deficient (TR-) Wistar rats; plasma, bile and urine samples were collected for 5 hr and analyzed by HPLC with radiochemical detection. The total radioactivity recovered in WT and TR- bile was 12% and 7% of the dose, respectively. NNAL-O-glucuronide accounted for 87% of the radioactivity in WT bile but was not detected in TR- bile. Urinary recovery of 1-(3-pyridyl)-1-butanol-4-carboxylic (hydroxy) acid, NNAL-O-glucuronide and NNAL-N-oxide from 2-5 hr was greater in TR- compared to WT rats. NNK plasma clearance was significantly higher in TR- (115 ± 23 ml/min/kg) compared to WT (48 ± 13 ml/min/kg) rats. A higher concentration and/or earlier appearance of hydroxy and keto acids, NNAL-N-oxide and NNK-N-oxide, and decreased NNK and NNAL concentrations, in TR- plasma suggested increased cytochrome P450 biotransformation in TR- rats. The total recovery of hydroxy acid in bile and urine was significantly higher in TR- compared to WT rats. Thus, Mrp2 is responsible for the biliary excretion of NNAL-O-glucuronide and Mrp2-deficiency results in increased concentrations of carcinogenic NNK metabolites.
Current affiliations: (EML) Department of Physiology, University of Alberta, Edmonton, AB, Canada; (GG) GlaxoSmithKline, Clinical Pharmacology and Discovery Medicine, Research Triangle Park, NC, USA; (KN) Shionogi & Co., Ltd., Development Research Laboratories, Toyonaka, Osaka, Japan
Received February 27, 2007; revised July 13, 2007; accepted August 13, 2007.
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