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 a distinctive tumor-specific expression pattern. The expression level of CYP2W1 is low or undetectable in both adult human liver tissues and extrahepatic tissues. In contrast to its absence or low expression in normal tissues, high expression of CYP2W1 was observed 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 endogenous substrates for CYP2W1 to understand the physiological roles that CYP2W1 may play in fetal development and cancer progression. We identify six endogenous substrates of CYP2W1: retinoic acid, retinol, retinal, arachidonic acid, farnesol, 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 three ligands. CYP2W1 readily converted all-trans retinoic acid (atRA) to 4-hydroxy atRA, 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. This work was supported by NIH grant GM25515.

Catalytic activities of tumor-specific human cytochrome P450 CYP2W1 towards endogenous substrates

251st National Meeting (2016)

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