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New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies

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New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies processes Review New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies Renata Mikstacka 1,* and Zbigniew Dutkiewicz 2,* 1 Department of Inorganic and Analytical Chemistry, Collegium Medicum, Nicolaus Copernicus University in Toru´n,Dr A. Jurasza 2, 85-089 Bydgoszcz, Poland 2 Department of Chemical Technology of Drugs, Pozna´nUniversity of Medical Sciences, Grunwaldzka 6, 60-780 Pozna´n,Poland * Correspondence: [email protected] (R.M.); [email protected] (Z.D.); Tel.: +48-52-585-3912 (R.M.); +48-61-854-6619 (Z.D.) Abstract: Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic heme-containing monooxy- genase. 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. Compu- tational 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. Keywords: cytochrome P450 1B1; CYP1B1 inhibitors; cancer chemoprevention and therapy; molecu- Citation: Mikstacka, R.; Dutkiewicz, lar docking; molecular dynamics simulations Z. New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies. Processes 2021, 9, 817. https://doi.org/10.3390/pr9050817 1. Introduction Cytochrome P450 enzymes (CYPs) are hemoproteins representing a superfamily of Academic Editor: Bonglee Kim monooxygenases responsible for the metabolism of endogenous and exogenous substrates. Human cytochrome P450 family 1 (CYP1) consists of three isoforms: CYP1A1, CYP1A2, and Received: 28 March 2021 CYP1B1. The family 1 member CYP1B1 is an extrahepatic enzyme expressed in hormone- Accepted: 3 May 2021 dependent tissues like the breast, prostate, ovaries, pancreas, and testis [1]. CYP1B1 Published: 8 May 2021 catalyzes oxidation and N- or O-dealkylation of xenobiotics including procarcinogens and environmental pollutants [2], and endogenous substrates such as fatty acids and steroids. Publisher’s Note: MDPI stays neutral CYP1B1 plays an important role in the pathogenesis of hormone-induced cancers, with regard to jurisdictional claims in being responsible for the metabolism of 17-alpha-estradiol (E2) to highly mutagenic and published maps and institutional affil- carcinogenic 4-hydroxy-E2 [3,4]. CYP1B1 overexpressed in cancer cells is partly respon- iations. sible for the resistance to anti-cancer drugs such as tamoxifen, paclitaxel and docetaxel, which are inactivated by this enzyme [5–7]. CYP1B1 is a tumor biomarker because of its overexpression in tumor cells derived from among others: breast, colon, lung skin, brain, and testis [8]. Therefore, the inhibition of CYP1B1 activity is considered a therapeutic target Copyright: © 2021 by the authors. for cancer chemoprevention and chemotherapy. On the other hand, the constitutively Licensee MDPI, Basel, Switzerland. overexpressed CYP1B1 in cancer cells and the tumor microenvironment may be used to This article is an open access article design anti-cancer prodrugs activated by this enzyme. Another pathway of CYP1B1 studies distributed under the terms and concerns the relation between mutations of the CYP1B1 gene and the occurrence of eye conditions of the Creative Commons diseases [9,10] and cardiovascular disorders [11] (Figure1). Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Processes 2021, 9, 817. https://doi.org/10.3390/pr9050817 https://www.mdpi.com/journal/processes Processes 2021, 9, x FOR PEER REVIEW 2 of 21 Processes 2021, 9, 817 2 of 20 FigureFigure 1. Cytochrome 1. Cytochrome P450 P450 1B1 1B1 functions functions and and its its association association with withpathogenesis pathogenesis of diseases. CYP1s are inducedCYP1s byare agonists induced ofby the agonists aryl hydrocarbon of the aryl hydrocarbon receptor (AhR), receptor including (AhR), including polychlorinatedpolychlorinated dioxins with strongdioxins inducer with strong 2,3,7,8-tetrachlorodibenzo-p-dioxin inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (TCDD) and polycyclicand aromatic polycyclic hydrocarbons aromatic hydrocarbons [12,13]. The [12,13]. role of The AhR role as of a transcriptionAhR as a transcription factor factor is is not limitednot to the limited metabolism to the metabolism of xenobiotics. of xenobiotics. The AhR The transduction AhR transduction pathway pathway is also is also acti- activated by endogenousvated by endogenous compounds, compounds, which include which the includ productse the of products metabolism of metabolism of polyun- of polyun- saturated fattysaturated acids and fatty heme, acids and and by heme, endobiotics—ligands and by endobiotics—ligands which are producedwhich are inproduced the in the gastrointestinalgastrointestinal tract and skin tract [14,15 and]. skin [14,15]. For a decade, epigeneticFor a decade, factors epigenetic affecting factors CYP1B1 affecting gene CY expressionP1B1 gene expression were studied were [16 studied]. [16]. Methylation ofMethylation cytosine residues of cytosine of genomic residues DNAof genomic of the DNA regulatory of the region(s)regulatory of region(s) a gene of a gene can lead to silencingcan lead or to diminished silencing or expression diminished of expression the gene. Studiesof the gene. of two Studies cell lines:of two MCF7 cell lines: MCF7 and HepB2, indicatedand HepB2, that indicated DNA methylation that DNA methylation diminished diminished the expression the expression of the CYP1B1 of the CYP1B1 gene in HepB2gene cells in [17 HepB2]. Differential cells [17]. regulation Differential of regulati the expressionon of the ofexpression CYP1B1 of and CYP1B1 CYP1B1 and CYP1B1 genes coding twogenes isoforms coding two of CYP1 isoforms was of observed CYP1 was in observ mouseed hepatoma in mouse andhepatoma fibroblast and cellfibroblast cell lines inducedlines by TCDD induced [18 ].by In TCDD gastric [18]. and In colorectalgastric and cancers, colorectal DNA cancers, methylation DNA methylation in the in the promotor regionpromotor of CYP1B1 region was of shownCYP1B1 [ 19was,20 shown]. [19,20]. This review presentsThis review the presents multiple the pharmacological multiple pharmacological roles of CYP1B1roles of CYP1B1 in a human in a human or- organism, emphasizingganism, emphasizing the latest achievements, the latest achievements, focusing on focusing the computational on the computational studies of studies of the molecular interactionsthe molecular of CYP1B1interactions with of its CYP1B1 substrates with and its inhibitors, substrates explaining and inhibitors, CYP1B1 explaining multiple functionsCYP1B1 at the multiple molecular functions level. at the molecular level. 2. The Role of2. CYP1B1 The Role in of the CYP1B1 Pathogenesis in the Pathogenesis of Diseases of Diseases CYP450 familyCYP450 1 isozymes family were 1 isozymes supposed were to supposed play an essential to play an role essential in cancer role initiation in cancer initiation by transformingby procarcinogens transforming procarcinogens into ultimate carcinogens, into ultimate which carcinogens, react with which DNA react and formwith DNA and DNA adducts.form Recent DNA studies adducts. indicate Recent that studies CYP1B1 indicate contributes that CYP1B1 to cancer contributes initiation, to andcancer to initiation, a significant extent,and to to a thesignificant following extent, stages to the of carcinogenesis:following stages promotion of carcinogenesis: and progression, promotion and pro- while the primarygression, role ofwhile CYP1A1 the primary and CYP1A2 role of isCYP1A1 detoxification and CYP1A2 of xenobiotics is detoxifica leadingtion of to xenobiotics activation of procarcinogens.leading to activation of procarcinogens. In the HumanIn Gene the Human Mutation Gene Database Mutation (http://www.hgmd.cf.ac.uk Database (http://www.hgmd.cf.ac.uk;; accessed on accessed 6 on 6 May 2021), 240May variants 2021), of240 the variants CYP1B1 of genethe CYP1B1 are listed. gene The are associationlisted. The association of their function of their function with the pathogenesiswith the pathogenesis of diseases in of humans diseases has in humans been recently has been intensively recently intensively studied [21 studied]. [21]. Molecular structures of pathogenic CYP1B1 mutant variants are analyzed in relation to Molecular structures of pathogenic CYP1B1 mutant variants are analyzed in relation to their impaired function with the use of the most advanced bioinformatics tools. their impaired function with the use of the most advanced bioinformatics tools. 2.1. CYP1B1 Contribution in Pathogenesis of Eye Diseases Processes 2021, 9, x. https://doi.org/10.3390/xxxxxGlaucoma is a group of eye diseases leading to the irreversible loss ofwww.mdpi.com/journal/processes vision. In the de- velopment of glaucoma, the CYP1B1 gene is involved: primary congenital glaucoma (PCG) Processes 2021, 9, 817 3 of 20 constitutes 55% of inherited pediatric onset
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