Abstract
Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic heme-containing monooxygenase. CYP1B1 contributes to the oxidative metabolism of xenobiotics, drugs, and endogenous substrates like melatonin, fatty acids, steroid hormones, and retinoids, which are involved in diverse critical cellular functions. CYP1B1 plays an important role in the pathogenesis of cardiovascular diseases, hormone-related cancers and is responsible for anti-cancer drug resistance. Inhibition of CYP1B1 activity is considered as an approach in cancer chemoprevention and cancer chemotherapy. CYP1B1 can activate anti-cancer prodrugs in tumor cells which display overexpression of CYP1B1 in comparison to normal cells. CYP1B1 involvement in carcinogenesis and cancer progression encourages investigation of CYP1B1 interactions with its ligands: substrates and inhibitors. Computational methods, with a simulation of molecular dynamics (MD), allow the observation of molecular interactions at the binding site of CYP1B1, which are essential in relation to the enzyme’s functions.
Highlights
Cytochrome P450 enzymes (CYPs) are hemoproteins representing a superfamily of monooxygenases responsible for the metabolism of endogenous and exogenous substrates.Human cytochrome P450 family 1 (CYP1) consists of three isoforms: CYP1A1, CYP1A2, and cytochrome P450 1B1 (CYP1B1)
This review presents the presents multiplethe pharmacological roles of CYP1B1 in a human ganism, emphasizing the latest achievements, focusing on the computational organism, emphasizing the latest achievements, focusing on the computational studies of studies o the molecular interactions with substrates and inhibitors, the molecular interactions of CYP1B1 withof its CYP1B1 substrates andits inhibitors, explaining
In order to explain the molecular basis of the variable phenotypes resulting from the CYP1B1 gene mutations, the subclones of twenty-three CYP1B1 missense variants occurring in glaucoma patients were examined by measuring in a cell system the dual activity of the enzyme to metabolize both retinol and 17β-estradiol
Summary
Cytochrome P450 enzymes (CYPs) are hemoproteins representing a superfamily of monooxygenases responsible for the metabolism of endogenous and exogenous substrates. CYP1B1 overexpressed in cancer cells is partly responsible for the resistance to anti-cancer drugs such as tamoxifen, paclitaxel and docetaxel, which are inactivated by this enzyme [5,6,7]. The constitutively overexpressed CYP1B1 in cancer cells and the tumor microenvironment may be used to design anti-cancer prodrugs activated by this enzyme. Another pathway of CYP1B1 studies concerns the relation between mutations of the CYP1B1 gene and the occurrence of eye diseases [9,10] and cardiovascular disorders [11] (Figure 1)
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