Cytochrome P450s in the development of target-based anticancer drugs

Purnapatre, Kedar; Khattar, Sunil K.; Saini, Kulvinder Singh

doi:10.1016/j.canlet.2007.10.024

Cited by 55 publications

(36 citation statements)

References 84 publications

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“…These latter efforts required optimal expression in bacteria and purification of the different CYP4B1 isoforms. It is widely recognized, inter alia for eukaryotic P450s and CPRs, that membrane-bound regions can severely reduce the yield of heterologous protein in E. coli (Purnapatre et al, 2008;Zelasko et al, 2013). Here, the idea is that the hydrophobicity of the N-terminal anchor of these enzymes and the absence of an inner membrane system impede efficient expression.…”

Section: Discussionmentioning

confidence: 99%

Ligand characterization of CYP4B1 isoforms modified for high-level expression inEscherichia coliand HepG2 cells

Roellecke

Jäger

Gyurov

et al. 2017

Protein Engineering, Design and Selection

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Human CYP4B1, a cytochrome P450 monooxygenase predominantly expressed in the lung, inefficiently metabolizes classical CYP4B1 substrates, such as the naturally occurring furan pro-toxin 4-ipomeanol (4-IPO). Highly active animal forms of the enzyme convert 4-IPO to reactive alkylating metabolite(s) that bind(s) to cellular macromolecules. By substitution of 13 amino acids, we restored the enzymatic activity of human CYP4B1 toward 4-IPO and this modified cDNA is potentially valuable as a suicide gene for adoptive T-cell therapies. In order to find novel pro-toxins, we tested numerous furan analogs in in vitro cell culture cytotoxicity assays by expressing the wildtype rabbit and variants of human CYP4B1 in human liver-derived HepG2 cells. To evaluate the CYP4B1 substrate specificities and furan analog catalysis, we optimized the N-terminal sequence of the CYP4B1 variants by modification/truncation and established their heterologous expression in Escherichia coli (yielding 70 and 800 nmol·l −1 of recombinant human and rabbit enzyme, respectively). Finally, spectral binding affinities and oxidative metabolism of the furan analogs by the purified recombinant CYP4B1 variants were analyzed: the naturally occurring perilla ketone was found to be the tightest binder to CYP4B1, but also the analog that was most extensively metabolized by oxidative processes to numerous non-reactive reaction products.

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Section: Discussionmentioning

confidence: 99%

Ligand characterization of CYP4B1 isoforms modified for high-level expression inEscherichia coliand HepG2 cells

Roellecke

Jäger

Gyurov

et al. 2017

Protein Engineering, Design and Selection

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“…Seven of the eight validated genes overexpressed in current smokers-CYP1B1, four AKRs, ALDH3A1, and NQO1 (Table 2)-are involved in drug and/or carcinogen metabolism (9,10,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Polycyclic aromatic hydrocarbons in tobacco smoke are known to bind to and activate the aryl hydrocarbon receptor and thus induce CYP1B1 (10).…”

Section: Discussionmentioning

confidence: 99%

“…Polycyclic aromatic hydrocarbons in tobacco smoke are known to bind to and activate the aryl hydrocarbon receptor and thus induce CYP1B1 (10). CYP1B1 expression is of special interest because it may contribute both to increased drug metabolism and to carcinogenesis of the aerodigestive tract (1,(18)(19)(20). The metabolic clearance of docetaxel, tamoxifen, gefitinib, erlotinib, and other cancer prevention and therapy drugs is enhanced by YP1B1 (9,(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Impact of Smoking Cessation on Global Gene Expression in the Bronchial Epithelium of Chronic Smokers

Zhang

Lee

Tang

et al. 2008

Cancer Prevention Research

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Cigarette smoke is the major cause of lung cancer and can interact in complex ways with drugs for lung cancer prevention or therapy. Molecular genetic research promises to elucidate the biological mechanisms underlying divergent drug effects in smokers versus nonsmokers and to help in developing new approaches for controlling lung cancer. The present study compared global gene expression profiles (determined via Affymetrix microarray measurements in bronchial epithelial cells) between chronic smokers, former smokers, and never smokers. Smoking effects on global gene expression were determined from a combined analysis of three independent data sets. Differential expression between current and never smokers occurred in 591 of 13,902 measured genes (P < 0.01 and >2-fold change; pooled data)-a profound effect. In contrast, differential expression between current and former smokers occurred in only 145 of the measured genes (P < 0.01 and >2-fold change; pooled data). Nine of these 145 genes showed consistent and significant changes in each of the three data sets (P < 0.01 and >2-fold change), with eight being down-regulated in former smokers. Seven of the eight down-regulated genes, including CYP1B1 and three AKR genes, influence the metabolism of carcinogens and/or therapeutic/chemopreventive agents. Our data comparing former and current smokers allowed us to pinpoint the genes involved in smoking-drug interactions in lung cancer prevention and therapy. These findings have important implications for developing new targeted and dosing approaches for prevention and therapy in the lung and other sites, highlighting the importance of monitoring smoking status in patients receiving oncologic drug interventions.

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“…Among many functions performed by the P450s, one of the most important is the drug biotransformation ability. Numerous studies have shown that the most active is CYP3A4 isoenzyme of P450 cytochrome, which metabolizes approximately 50% of all drugs [16].…”

Section: Methods Used In Drug Metabolism Studiesmentioning

confidence: 99%

Photocatalysis combined with chromatographic methods as a new promising tool in drug metabolism studies – a review

Gawlik

Skibiński

Trawiński

et al. 2018

Acta Chromatographica

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The number of new drugs launched to the market is constantly increasing; however, the metabolism of many of them is still not fully established. The knowledge of drug metabolism pathways is crucial for the efficacy and safety of therapies and, in classical approach, requires the use of animals as well as human volunteers, but this kind of research is expensive and time-consuming. Therefore, nowadays, more and more biological and chemical in vitro methods are developed for the drug metabolism study. This review is focused on the photocatalytic degradation of chemicals and the application of this process in chromatographic methods of drug metabolism research. A theoretical background of photocatalysis and all its applications in a drug metabolism study were reviewed, and other in vitro methods that are actually used were summarized and discussed. Other analytical methods used in this area were also discussed and compared.

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Cytochrome P450s in the development of target-based anticancer drugs

Cited by 55 publications

References 84 publications

Ligand characterization of CYP4B1 isoforms modified for high-level expression inEscherichia coliand HepG2 cells

Ligand characterization of CYP4B1 isoforms modified for high-level expression inEscherichia coliand HepG2 cells

Impact of Smoking Cessation on Global Gene Expression in the Bronchial Epithelium of Chronic Smokers

Photocatalysis combined with chromatographic methods as a new promising tool in drug metabolism studies – a review

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