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.
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, [(3)H]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.
Leslie
Elaine M
EM
School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Ghibellini
Giulia
G
Nezasa
Ken-Ichi
K
Brouwer
Kim L R
KL
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D001646:Bile / Q000378:metabolism; D001652:Bile Ducts; D001692:Biological Transport; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics*; D003497:Cyclic N-Oxides / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D009602:Nitrosamines / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
C526964:3-(4-(methylnitrosoamino)-1-hydroxybutyl)pyridine N-oxide; C099564:4-((methylnitrosoamino)-1-(3-pyridyl)but-1-yl)beta-omega-glucosiduronic acid; C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D002273:Carcinogens; D003497:Cyclic N-Oxides; D005965:Glucuronates; D000089762:Multidrug Resistance-Associated Protein 2; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone