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Tissue Specificity for Mutation Parallels Tissue Specificity for Cancer

.2, 2.4, and 2.1 fold, respectively). In contrast, they observed no statistically significant mutation induction in nontarget tissues such as the urinary bladder (1.7 x 10-5 versus 1.4 x 10-5 in controls), testis (0.39 x 10-5 versus 0.48 x 10-5 in controls), and bone marrow (1.7 x 10-5 versus 1.3 x 10-5 in controls).

MeIQ

MeIQ (2-amino-3,4-dimethylimidazo[4,5-f ]quinoline) is a potent heterocyclic amine found in the human diet. MeIQ induces tumors in several rat tissues including colon, skin, mammary gland, oral cavity; in the mouse it forms tumors of the forestomach and liver. Several publications have shown that MeIQ induced mutations in Big Blue transgenic rodents.4,5 Induced mutations have been observed in each target tissue except the heart, which is not a target for tumorigenesis. Ushijima et al.5 determined the DNA sequence alterations in mutants recovered from the liver (approximately a 4.5-fold increase in mutant frequency) and bone marrow (approximately a 5-fold increase). A significant tissue-specific difference was seen in the mutant fractions that were GC to TA transversions: 37% in the liver versus only 14% in bone marrow. Consequently, both sequencing DNA and determining mutant frequency are important for more accurately assessing mutation induction and mechanism.

PhIP

PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is a colon carcinogen in the male rat but does not cause tumors in the liver. It induced a 20-fold increase in colon mutations after 400 ppm PhIP was added to the diet.6 We recently determined that no mutations above background are induced in the liver of these animals (de Boer, et al., unpublished). DNA adducts are found in the colon but not the liver. PhIP is metabolically activated in the liver by cytochrome P450, but additional metabolic processin
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