Chapter 5 Cancer and benign tumours/Fig 5.28.jpg

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(1) A genotoxin may directly interact with DNA or do so following metabolic activation, e.g. by one of the cytochrome P450 enzymes. DNA adducts are formed or direct DNA strand breakage occurs. (2) Defective DNA repair may result in mutations which affect key genes such as those involved in regulating the cell cycle, apoptosis or differentiation leading to tumour formation. (3) Non-genotoxins do not have direct effects on DNA but cause cell proliferation by deregulating normal cell cycle activity. (4) Many of the enzymes involved are polymorphic, that is there is a sequence variation in the gene that may reflect a change in expression, inducibility of the gene or function. At each stage of metabolism there is variability between individuals in terms of exposure levels and also the metabolic activity determined both by the genotype of the individual and level of expression and function of the enzymes. GST = glutathione S-transferase.