Metabolism of food-derived heterocyclic amines in human and rabbit tissues by P4503A proteins in the presence of flavonoids.
The ability of human and rabbit gastrointestinal-tract microsomes to metabolize the heterocyclic amine 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) to a mutagen was determined with the Ames test. When human jejunal and ileal microsomes were used as the metabolic activation source, MeIQ produced 1675 and 388 revertants/mg of microsomal protein, respectively, and this increased to 29,230 and 17,963 revertants/mg of microsomal protein, respectively, in the presence of 100 microM alpha-naphthoflavone. MeIQ in the presence of control rabbit duodenal, jejunal, and ileal microsomes produced 2304 +/- 1018, 988 +/- 386, and 444 +/- 134 (mean +/- SD, four samples) revertants/mg of microsomal protein, respectively. In the presence of alpha-naphthoflavone (100 microM), these activities increased greater than 7-fold. P4503A proteins were detectable on Western blots of microsomes prepared from both human and rabbit small intestine. Further, rifampicin-induced rabbit hepatic-microsomal activation of MeIQ was completely inhibited at low concentrations of alpha-naphthoflavone, but at higher concentrations (i.e., 100 microM) this returned to control levels. Flavone also caused a marked stimulation of MeIQ activation in human and rabbit gastrointestinal-tract microsomes. The aforementioned data suggest that flavonoids markedly increase the ability of P4503A isozymes to activate heterocyclic amines to mutagens in the Ames test.
McKinnon
R A
RA
Department of Clinical Pharmacology, School of Medicine, Flinders University of South Australia, Bedford Park.
Burgess
W M
WM
Hall
P M
PM
Abdul-Aziz
Z
Z
McManus
M E
ME
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology*; D001711:Biotransformation / Q000187:drug effects; D002432:Cecum / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics*; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D009153:Mutagens / Q000493:pharmacokinetics*; D011804:Quinolines / Q000493:pharmacokinetics*; D011817:Rabbits
D001571:Benzoflavones; D006571:Heterocyclic Compounds; D009153:Mutagens; D011804:Quinolines; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline