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CYP1A2-catalyzed Conversion of Dietary Heterocyclic Amines to Their Proximate Carcinogens Is Their Major Route of Metabolism in Humans¹

Department of Clinical Pharmacology, Royal Postgraduate Medical School, Du Cane Road, London W12 0NN, UK [A.R.B., A.M.L., S.M., N.J.G., D.S.D.], and Department of Clinical Pharmacology/Toxicology, Consori d'Hospitals de Barcelona, Institut Municipal d'lnvestigació Mèdica, Passeig Maritim, Barcelona 08003, Spain [R.d.I.Z, A.S., M.F.,J.S.]

² To whom requests for reprints should be addressed, at Department of Clinical Pharmacology, Royal Postgraduate Medical School, Du Cane Rd., London W12 ONN, England.

The contribution of CYP1A2 to the metabolism of the dietary heterocyclic 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 humans, has been determined with furafylline, a highly selective inhibitor of this enzyme. The inhibitory potential of furafylline in vivo was first assessed by determining its effect on clearance of phenacetin to paracetamol by the model CYP1A2-dependent O-deethylation pathway. Furafylline inhibited this reaction by >99% in all subjects, thus demonstrating 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 crossover design, 2 h prior to consuming a test meal of fried beef containing a known amount of amines. The excretion of PhIP and MeIQx in urine was determined during the subsequent 28 h, using gas chromatography-mass spectrometry. Following furafylline, the excretion of unchanged MeIQx increased 14.3-fold, while that of PhIP increased 4.1-fold (P < 0.01, paired t test). Elimination of both amines was first order and very rapid, with half-lives of <5 h. The elimination rate constants did not change following furafylline, suggesting that total clearance is limited by hepatic blood flow. Because the elimination of the amines was first order, it was possible to calculate the contribution of CYP1A2 to the clearance of the amines. CYP1A2-catalyzed metabolism accounts for 91% of the elimination of ingested MeIQx and 70% of ingested PhIP, most likely via N-hydroxylation.

¹ Work carried out at the Royal Postgraduate Medical School was supported by grants awarded by the National Cancer Institute, Department of Health and Human Services (PHS Grant CA40895-02), Ministry of Agriculture, Fisheries, and Food, and the Cancer Research Campaign. Work at the Institut Municipal d'Investigació Mèdica was supported by the British-Spanish Joint Research Programme and by the Comisión Interministerial de Ciencia y Tecnologóa (Project SAL91-0839).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/22/93. Accepted 11/ 1/93.

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