Prenylflavonoids from hops inhibit the metabolic activation of the carcinogenic heterocyclic amine 2-amino-3-methylimidazo[4,5-F] quinoline, mediatedby cDNA-expressed human CYP1A2

The heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a po tential human carcinogen found in cooked food that requires initial metabol ic activation by cytochrome P450s, primarily CYP1A2. The present study was conducted to examine whether recombinant human CYP1A2 expressed in insect c ells mediates the metabolic activation of IQ and whether prenylflavonoids f ound in hops and beer would modulate the CYP1A2-mediated activation of IQ. The cDNA-expressed human CYP1A2 was found to strongly activate IQ as measur ed by the Ames Salmonella assay and by the covalent binding of IQ metabolit es to calf thymus DNA and protein. Inhibition studies showed that the preny lchalcone xanthohumol and the prenylflavanones 8-prenylnaringenin and isoxa nthohumol strongly inhibited the mutagenic activation of IQ mediated by cDN A-expressed human CYP1A2 in the Ames Salmonella assay. The three prenylflav onoids also markedly inhibited the human CYP1A2-mediated binding of IQ to m etabolites that bind to DNA. The inhibition of the metabolic activation of IQ was paralleled by the inhibition of acetanilide 4-hydroxylase activity o f human CYP1A2. Thus, xanthohumol, isoxanthohumol, and prenylflavanones 8-p renylnaringenin are potent inhibitors of the metabolic activation of IQ and may have the potential to act as chemopreventive agents against cancer ind uced by heterocyclic amines activated by CYP1A2.