Carcinogenesis Advance Access originally published online on August 27, 2007
Carcinogenesis 2007 28(12):2650-2656; 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
1 School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
2 Present address: Membrane protein research group Department of Physiology, University of Alberta, Edmonton, AB T6G 2H7, Canada
3 Present address: Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Research Triangle Park, NC 27709, USA
4 Present address: Development Research Laboratories, Shionogi & Co., Ltd, Toyonaka, Osaka 561-0825, Japan
* To whom correspondence should be addressed. Tel: +1 919 962 7030; Fax: +1 919 966 0197; Email: kbrouwer{at}unc.edu
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 multidrug resistance protein (MRP)1 (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 h and analyzed by high-pressure liquid chromatography 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 acid (hydroxy acid), NNAL-O-glucuronide and NNAL-N-oxide from 2–5 h was greater in TR– compared with WT rats. NNK plasma clearance was significantly higher in TR– (115 ± 23 ml/min/kg) compared with WT (48 ± 13 ml/min/kg) rats. A higher concentration and/or earlier appearance of hydroxy and 1-(3-pyridyl)-1-butanone-4-carboxylic 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 with WT rats. Thus, Mrp2 is responsible for the biliary excretion of NNAL-O-glucuronide and Mrp2 deficiency results in increased formation of carcinogenic NNK metabolites.
Abbreviations: ABC, ATP-binding cassette; CL, clearance; CLbiliary, biliary clearance; CLrenal, renal clearance; CYP450, cytochrome P450; HPLC, high-pressure liquid chromatography; hydroxy acid, 1-(3-pyridyl)-1-butanol-4-carboxylic acid; keto acid, 1-(3-pyridyl)-1-butanone-4-carboxylic acid; MRP, multidrug resistance protein; MW, molecular weight; NNAL, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; WT, wild-type
Received February 27, 2007; revised July 13, 2007; accepted August 13, 2007.
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