Cytochromes P450 are a superfamily of heme proteins involved in oxidative metabolism of endogenous chemicals such as steroid hormones and human-made xenobiotics including drugs and environmental pollutants. Hundreds of P450s have been demonstrated by cDNA and gene cloning in animals, plants, fungi, and bacteria. Most of the mammalian xenobiotic-metabolizing P450s, found within the eight subfamilies comprising the CYP2 family, are constitutively expressed in the liver. Transcriptional activation of individual P450 genes in the liver commences at distinct stages of development. Some P450 genes are preferentially expressed in one sex. The mechanisms of liver-specific expression of the P450 genes are quite diverse. Recent studies have found that several different liver-enriched transcription factors including HNF-1 alpha, HNF-3, HNF-4, and C/EBP beta, and the more ubiquitously expressed factors Sp1, GABP alpha/beta, and NF2d9 are responsible for governing the transcription of P450 genes. In some cases, more than one factor can influence expression depending on the developmental stage of the animal, and ubiquitously expressed factors such as Sp1 have been found to cooperate with liver-enriched factors to maximally activate transcription of P450 genes. STAT protein- and phospholipase A2-mediated signal transduction have also been implicated in sex-dependent expression of certain P450 genes. These studies indicate that P450 genes, even within the same subfamily in the same mammalian species, can have unique regulatory circuits.-Gonzalez, F. J., Lee, Y.-H. Constitutive expression of hepatic cytochrome P450 genes.