Inter-Individual Variation in the Metabolic Activation of Heterocyclic Amines and Susceptibility to Prostate Cancer
Final rept. 17 Jun 2002-16 Jun 2005
UNIVERSITY OF MEDICINE AND DENTISTRY OF NEW JERSEY NEWARK
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The etiology of human prostate cancer is not well understood. Epidemiological studies suggest that exposure to carcinogenic heterocyclic amines RCA such as PhIP formed in high-temperature cooked meatfish is an important risk factor. The Phase 1 metabolism of PhIP in human is mainly catalyzed by CYP enzymes, which leads to the formation of 2-hydroxamino-PhIP N-hydroxy PhIP, the carcinogenic, metabolite, and 4-hydroxy PhIP 4-hydroxy PhIP, the non-carcinogenic metabolite. In the present study, we established a highly sensitive LCMS method and used it to determine the capability of human prostate tissues n31 in metabolizing PhIP and other carcinogenic HCA. Our results indicate that there is no significant N- hydroxylation of PhIP, IQ, MeIQ and MeIQx in human prostate microsomes. We also characterized the functional significance of 15 polymorphic variants of CYP1B1 which is a major human enzyme for PhIP metabolic activation in extrahepatic tissues. Results of our study provide important information on the understanding of inter-individual, susceptibility to prostate cancer.
- Medicine and Medical Research