Metabolism of nicotine and induction of CYP1A forms in precision-cut rat liver and lung slices.
The aim of this study was to investigate xenobiotic metabolism and induction of cytochrome P450 (CYP) forms in precision-cut rat liver and lung slices, employing nicotine as a model compound. Freshly cut rat liver and lung slices metabolised nicotine to the major metabolite cotinine. Observed Km values for cotinine formation in liver and lung slices were 323 and 41.7 microM, respectively, with corresponding V(max) values of 47.2 and 3.21 pmol/min/mg protein, respectively. Rat liver and lung slices were cultured for 48 h with Aroclor 1254, benzo(a)pyrene, nicotine and cotinine. Both Aroclor 1254 and benzo(a)pyrene produced a marked induction of CYP1A-dependent 7-ethoxyresorufin O-deethylase activity in both liver and lung slices. However, while nicotine induced 7-ethoxyresorufin O-deethylase activity in lung slices, but not in liver slices, cotinine did not induce enzyme activity in either liver or lung slices. Overall, while higher rates of nicotine metabolism were observed in rat liver slices, nicotine-induced CYP1A form induction was observed in lung slices. These results demonstrate the usefulness of precision-cut tissue slices for studying tissue differences in xenobiotic metabolism and CYP form induction.
Price
Roger J
RJ
BIBRA International Ltd., Woodmansterne Road, Carshalton, Surrey SM5 4DS, UK.
Renwick
Anthony B
AB
Walters
David G
DG
Young
Philip J
PJ
Lake
Brian G
BG
D000818:Animals; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008168:Lung / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009538:Nicotine / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D018722:Nicotinic Agonists; D009538:Nicotine; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1