Carcinogenesis Advance Access originally published online on April 8, 2004
Carcinogenesis 2004 25(9):1659-1669; doi:10.1093/carcin/bgh164
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Carcinogenesis vol.25 no.9 © Oxford University Press 2004; all rights reserved.
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Cruciferous vegetable consumption alters the metabolism of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans
1 BIBRA International Ltd, Woodmansterne Road, Carshalton, Surrey SM5 4DS, UK, 2 Centre for Toxicology, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK, 3 Molecular Toxicology, Biomedical Sciences, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK, 4 Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, PO Box 808, L-452 Livermore, CA 94551, USA and 5 Experimental Medicine and Toxicology, Division of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK
6 To whom correspondence should be addressed Email: blake{at}bibra.co.uk
Consumption of red meat is associated with an increased risk of colorectal cancer, whereas cruciferous vegetable consumption reduces cancer risk. While the mechanisms remain to be determined, cruciferous vegetables may act by altering the metabolism of carcinogens present in cooked food, such as the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The aim of this study was to evaluate the effect of cruciferous vegetable consumption on the metabolism of PhIP in 20 non-smoking Caucasian male subjects. The study consisted of three 12-day phases, namely two periods of avoidance of cruciferous vegetables (phases 1 and 3) and a high cruciferous vegetable diet period (phase 2), when subjects ingested 250 g each of Brussels sprouts and broccoli per day. At the end of each study phase, the subjects consumed a cooked meat meal containing 4.90 µg PhIP and urine samples were collected for up to 48 h. Cruciferous vegetable consumption significantly increased hepatic CYP1A2, as demonstrated by changes in saliva caffeine kinetics. Samples of N2-hydroxy-PhIP-N2-glucuronide (the major urinary metabolite of PhIP in humans), N2-hydroxy-PhIP-N3-glucuronide and their trideuterated derivatives (to serve as internal standards) were synthesized and a liquid chromatography-mass spectrometry-mass spectrometry method developed for their analysis. In phases 1 and 3, the excretion of N2-hydroxy-N2-PhIP-glucuronide in 0–48 h urine samples was six times that of N2-hydroxy-PhIP-N3-glucuronide. Cruciferous vegetable consumption significantly increased the urinary excretion of N2-hydroxy-PhIP-N2-glucuronide in 0–48 h urine samples to 127 and 136% of levels observed in phases 1 and 3, respectively. In contrast, the urinary excretion of N2-hydroxy-PhIP-N3-glucuronide was unchanged. While the urinary excretion of both PhIP metabolites accounted for 
39% of the PhIP dose in phases 1 and 3, they accounted for 49% of the dose in phase 2. This study demonstrates that cruciferous vegetable consumption can induce both the phase I and II metabolism of PhIP in humans.
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