Endogenous Substrates for Tumor‐Specific Human Cytochrome P450 CYP2W1

Human cytochrome P450 enzymes play an important role in the metabolism of steroids, vitamins, eicosanoids, fatty acids and xenobiotics. CYP2W1 is a recently‐discovered human cytochrome P450 enzyme with low or undetectable expression in both adult human liver tissues and extrahepatic tissues, but high expression in human fetal tissues and in many tumor samples, especially colon and adrenal tumors. The distinctive expression pattern of CYP2W1, which features high expression in fetal and tumor tissues, but no expression in normal adult tissues, suggests that the cancer‐specific expression of CYP2W1 might be related to reversion to more primitive, embryonic cell types in which it had specific physiological roles. In this study we explored the physiological function of CYP2W1 in fetal development and cancer progression by searching for its endogenous substrates. We identified seven endogenous ligands that exhibited binding affinities to CYP2W1: retinoic acid, retinol, retinal, arachidonic acid, farnesol, geranylgeraniol and 17β‐estradiol. CYP2W1 exhibited tight binding affinities for retinoids, which have low nanomolar binding constants, and much poorer binding constants in the micromolar range for the other four ligands. CYP2W1 readily converted all‐ trans retinoic acid ( at RA) to 4‐hydroxy at RA, all‐ trans retinol to 4‐OH all‐ trans retinol, and also readily oxidized retinal. The enzyme much less efficiently oxidized arachidonic acid to 8,9‐diHETrE, 11,12‐diHETrE and 14,15‐diHETrE, 17β‐estradiol to 2‐hydroxy‐(17β)‐estradiol, and farnesol to a monohydroxylated product. These findings indicate that CYP2W1 probably plays an important role in localized retinoid metabolism that may be intimately linked to its involvement in tumor development. Support or Funding Information This work was supported by NIH grant GM25515.