CYP1A2-CATALYZED CONVERSION OF DIETARY HETEROCYCLIC AMINES TO THEIR PROXIMATE CARCINOGENS IS THEIR MAJOR ROUTE OF METABOLISM IN HUMANS

The contribution of CYP1A2 to the metabolism of the dietary heterocycl ic amines, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in vivo in human s, has been determined with furafylline, a highly selective inhibitor of this enzyme. The inhibitory potential of furafylline in vivo was fi rst assessed by determining its effect on clearance of phenacetin to p aracetamol by the model CYP1A2-dependent O-deethylation pathway. Furaf ylline inhibited this reaction by >99% in all subjects, thus demonstra ting its applicability to determining the contribution of CYP1A2 to a given reaction in vivo. A group of 6 healthy male volunteers received either placebo or 125 mg furafylline, in a double-blind balanced cross over design, 2 h prior to consuming a test meal of fried beef containi ng a known amount of amines. The excretion of PhIP and MeIQx in urine was determined during the subsequent 28 h, using gas chromatography-ma ss spectrometry. Following furafylline, the excretion of unchanged MeI Qx increased 14.3-fold, while that of PhIP increased 4.1-fold (P < 0.0 1, paired t test). Elimination of both amines was first order and very rapid, with half-lives of <5 h. The elimination rate constants did no t change following furafylline, suggesting that total clearance is lim ited by hepatic blood flow. Because the elimination of the amines was first order, it was possible to calculate the contribution of CYP1A2 t o the clearance of the amines. CYP1A2-catalyzed metabolism accounts fo r 91% of the elimination of ingested MeIQx and 70% of ingested PhIP, m ost likely via N-hydroxylation.