Prenylflavonoids from hops inhibit the metabolic activation of the carcinogenic heterocyclic amine 2-amino-3-methylimidazo[4, 5-f]quinoline, mediated by cDNA-expressed human CYP1A2.
The heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potential human carcinogen found in cooked food that requires initial metabolic activation by cytochrome P450s, primarily CYP1A2. The present study was conducted to examine whether recombinant human CYP1A2 expressed in insect cells mediates the metabolic activation of IQ and whether prenylflavonoids found in hops and beer would modulate the CYP1A2-mediated activation of IQ. The cDNA-expressed human CYP1A2 was found to strongly activate IQ as measured by the Ames Salmonella assay and by the covalent binding of IQ metabolites to calf thymus DNA and protein. Inhibition studies showed that the prenylchalcone xanthohumol and the prenylflavanones 8-prenylnaringenin and isoxanthohumol strongly inhibited the mutagenic activation of IQ mediated by cDNA-expressed human CYP1A2 in the Ames Salmonella assay. The three prenylflavonoids also markedly inhibited the human CYP1A2-mediated binding of IQ to metabolites that bind to DNA. The inhibition of the metabolic activation of IQ was paralleled by the inhibition of acetanilide 4-hydroxylase activity of human CYP1A2. Thus, xanthohumol, isoxanthohumol, and prenylflavanones 8-prenylnaringenin are potent inhibitors of the metabolic activation of IQ and may have the potential to act as chemopreventive agents against cancer induced by heterocyclic amines activated by CYP1A2.
Miranda
C L
CL
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331-7301, USA.
Yang
Y H
YH
Henderson
M C
MC
Stevens
J F
JF
Santana-Rios
G
G
Deinzer
M L
ML
Buhler
D R
DR
D000818:Animals; D001711:Biotransformation / Q000187:drug effects*; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics*; D002384:Catalysis; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D018076:DNA, Complementary; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D009152:Mutagenicity Tests; D010944:Plants / Q000737:chemistry*; D011485:Protein Binding; D011804:Quinolines / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012486:Salmonella typhimurium / Q000235:genetics; D018411:Spodoptera
D002273:Carcinogens; D018076:DNA, Complementary; D005419:Flavonoids; D011804:Quinolines; D011994:Recombinant Proteins; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D019388:Cytochrome P-450 CYP1A2