METABOLISM OF RETINOIDS AND ARACHIDONIC ACID BY HUMAN AND MOUSE CYTOCHROME P450 1B1

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Abstract
The cytochrome P450 family 1 (CYP1) is considered to be one of the xenobiotic-metabolizing enzyme families and is responsible for oxidative metabolism of polycyclic aromatic hydrocarbons. For example, mouse Cyp1b1 was originally identified as the enzyme responsible for oxidative metabolism of 7,12-dimethylbenz(α)anthracene (DMBA). A comparison of the kinetics of this metabolism by mouse and human CYP1B1 orthologs revealed the mouse enzyme to have a more favorable metabolism of DMBA, with a catalytic efficiency ratio (CER) of 0.23. However, CYP1 enzymes are also capable of metabolism of endobiotics, and in the present study, the metabolism of retinoids and lipid endobiotics by human CYP1B1 and mouse Cyp1b1 orthologs was compared. Both hemoproteins oxidized retinol to retinal and retinal to retinoate, but did not oxidize retinoate. The CYP1B1 to Cyp1b1 CERs were 13 and 26 for the two steps, respectively; the Cyp1b1 Km(app) values for retinoids were 20-fold higher. Human family 1 cytochromes P450 had unique regional specificities for arachidonate oxidation: the major metabolites of CYP1A1, CYP1A2, and CYP1B1 were 75% terminal hydroxyeicosatetraenoic fatty acids (HETEs), 52% epoxyeicosatrienoic fatty acids (EETs), and 54% mid-chain HETEs, respectively. CYP1A1 and CYP1B1 Km(app) values for arachidonate were about 30 μM, whereas CYP1A2 Km(app) was 95 μM. The major metabolites of arachidonic acid by Cyp1b1 were EETs (50%) and midchain HETEs (37%). The mouse ortholog had a CER for metabolite production of 64 due to a Km(app) of 0.5 mM for arachidonate.

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