P450 genes: evolution, regulation, and relationship to human cancer and pharmacogenetics.

Three pharmacogenetic differences (the acetylation, debrisoquine 4-hydroxylase, and Ah locus polymorphisms) appear to be associated with increased risk of environmentally caused human cancer. The latter two polymorphisms represent differences in P450 gene expression. It is predicted that molecular biological studies will soon provide a means (RFLP patterns or expression vector assays) of predicting individual cancer risk related to these polymorphisms. At the present time, only the Ah locus polymorphism has been explored at the molecular biological level. More than 30 P450 genes, including eight from the human, have been isolated and sequenced to date. The P450 gene superfamily comprises at least eight families, including one gene family that has diverged more recently into at least five subfamilies. The P450 gene superfamily can be regarded as ancient, with Pseudomonas and human amino acid sequences displaying a small but significant resemblance in the region of the enzyme active-site. P450 enzymic activity can be depressed 30-60% by immunosuppressive agents. The mechanism of this effect is unknown. This phenomenon can become clinically important if a cancer patient who is taking any chemotherapeutic drug that is detoxified by P450 then receives one of these agents. The Ah receptor-controlled gene expression, positive and negative control elements, and negative autoregulatory loop--best characterized in the mouse P(1)450 gene and upstream sequences, plus the receptor-defective and the P(1)450 enzymic activity-negative mutants in mouse cell cultures--provide the molecular geneticist with an exciting model system for studying the regulation of a clinically relevant gene family. The high degree of homology in a 220-bp segment between mouse and human P(1)450 sequences (about 1140 to 920 bases upstream from the mRNA cap site) suggests that this positive regulatory element (dioxin-inducible enhancer which also controls constitutive gene expression) is conserved between Mus domesticus and Homo sapiens.