Genetically determined differences in the response to carcinogens of aryl hydrocarbon hydroxylase and ornithine...

Carcinogenesis involves a complex interplay of both hereditary and environmental factors. With the exception of some cancers which may be inherited through an autosomal dominant gene (e.g., retinoblastoma), cancer causation is controlled by a multitude of genes. The murine Ah complex is an example of a well-characterized model system for studying genetic factors for carcinogenesis in mice. The Ah complex controls the induction of several xenobiotic-metabolizing enzyme activities by, e.g., polycyclic aromatic hydrocarbons (PAHs). Allelic differences at the Ah locus are associated with increased individual risk for cancer and mutation. The polyamines and their biosynthetic enzymes, especially ornithine decarboxylase (ODC), are useful probes in the study of carcinogenesis. The available evidence supports the theory that the induction of ODC activity is an essential factor in mouse skin tumorigenesis. In contrast, ODC induction is not an essential prerequisite in the induction of enzymes involved in converting carcinogens of the PAH-type to reactive intermediates capable of binding to DNA. The possible involvement of the polyamines and ODC in cancer initiation and promotion, in DNA repair processes and in genetic factors that might influence them are discussed in this review.