Cytochrome P450 genes (CYPs) encoding two new subfamilies designated CYP4X1 and CYP4Z1 were identified in the human genome and the Expressed Sequence Tags database. Partial cDNAs encoding both P450s were isolated from human kidney and used to determine tissue distribution. CYP4X1 was predominantly expressed in trachea and aorta, whereas CYP4Z1 mRNA was preferentially expressed in mammary tissue. In T47-D cells, CYP4Z1 mRNA levels were induced by dexamethasone (14-fold) or by progesterone (10-fold). The induction by these compounds was suppressed by co-treatment with the progesterone and glucocorticoid receptor antagonist mifepristone (RU486). In the progesterone receptor negative MCF-7 cells, CYP4Z1 mRNA was induced by dexamethasone but not by progesterone treatment. CYP4Z1 mRNA levels were unaffected by 17beta-estradiol. In confluent cultures of human hepatoma HepG2 cells that stably express a mouse peroxisome proliferator activated receptor-alpha (PPARalpha) mutant, CYP4X1 mRNA was undetectable in vehicle-treated cells but was readily detectable following addition of the PPARalpha agonist Wy14643. This suggests that PPARalpha activation can affect human CYP4X1 gene transcription. These results demonstrate selective tissue expression and implicate PPARalpha in CYP4X1 regulation, and the glucocorticoid and progesterone receptors in CYP4Z1 gene activation.