Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism

Leveraging New Plans in AgentSpeak(PL)

Many papers have been written on the anticancer properties of dietary flavonoids, and a range of potential mechanisms of action of flavonoids. However, most dietary flavonoids - notably polyphenolic flavonoids—have very poor ADME properties, and the levels necessary to stop growth of tumour cells cannot be sustained in a human body trough dietary intake alone. At present no flavonoid based drugs are clinically used in cancer therapy. Thus, whereas epidemiological and pre-clinical data seem to indicate a high potential for flavonoids, from the point of view of the pharmaceutical industry and drug developers, they are considered poor candidates. The flavones—which constitute a subgroup of the flavonoids—show some structural analogy with oestrogen and are known to interact with human oestrogen receptors, either as agonist or as antagonist. They are classed as phytoestrogens, and may play a role in cancer prevention through a mechanism of action possibly similar to that of the clinically used medication tamoxifen. Flavones are abundantly present in common fruits and vegetables, many of which have been associated with cancer prevention. Their phytoestrogen activity makes that they can assert their biological action at concentrations that are realistically achievable in the human systemic circulation

Physiological and anthocyanin biosynthesis genes response induced by vanadium stress in mustard genotypes with distinct photosynthetic activity

The present study aimed to elucidate the photosynthetic performance, antioxidant enzyme activities, anthocyanin contents, anthocyanin biosynthetic gene expression, and vanadium uptake in mustard genotypes (purple and green) that differ in photosynthetic capacity under vanadium stress. The results indicated that vanadium significantly reduced photosynthetic activity in both genotypes. The activities of the antioxidant enzymes were increased significantly in response to vanadium in both genotypes, although the purple exhibited higher. The anthocyanin contents were also reduced under vanadium stress. The anthocyanin biosynthetic genes were highly expressed in the purple genotype, notably the genes TT8, F3H, and MYBL2 under vanadium stress. The results indicate that induction of TT8, F3H, and MYBL2 genes was associated with upregulation of the biosynthetic genes required for higher anthocyanin biosynthesis in purple compared with the green mustard. The roots accumulated higher vanadium than shoots in both mustard genotypes. The results indicate that the purple mustard had higher vanadium tolerance

Expression Profile of CYP1A1 and CYP1B1 Enzymes in Colon and Bladder Tumors

<div><p>Background</p><p>The cytochrome P450 CYP1A1 and CYP1B1 enzymes are involved in carcinogenesis via activation of pro-carcinogenic compounds to carcinogenic metabolites. CYP1A1 and CYP1B1 have shown elevated levels in human tumors as determined by qRT-PCR and immunohistochemical studies. However studies that have examined CYP1 expression by enzyme activity assays are limited. </p> <p>Results</p><p>In the current study the expression of CYP1A1 and CYP1B1 was investigated in a panel of human tumors of bladder and colorectal origin by qRT-PCR and enzyme activity assays. The results demonstrated that 35% (7/20) of bladder tumors and 35% (7/20) of colon tumors overexpressed active CYP1 enzymes. CYP1B1 mRNA was overexpressed in 65% and 60% of bladder and colon tumors respectively, whereas CYP1A1 was overexpressed in 65% and 80% of bladder and colon tumors. Mean mRNA levels of CYP1B1 and CYP1A1 along with mean CYP1 activity were higher in bladder and colon tumors compared to normal tissues (p<0.05). Statistical analysis revealed CYP1 expression levels to be independent of TNM status. Moreover, incubation of tumor microsomal protein in 4 bladder and 3 colon samples with a CYP1B1 specific antibody revealed a large reduction (72.5 ± 5.5 % for bladder and 71.8 ± 7.2% for colon) in catalytic activity, indicating that the activity was mainly attributed to CYP1B1 expression. </p> <p>Conclusions</p><p>The study reveals active CYP1 overexpression in human tumors and uncovers the potential use of CYP1 enzymes and mainly CYP1B1 as targets for cancer therapy. </p> </div

Expression profiling of CYP1A1 and CYP1B1 mRNA in bladder samples.

<p>qRT-PCR analysis of CYP1B1 and CYP1A1 in 20 matched normal and tumor pairs derived from bladder tissue. Each bar represents an average of triplicate reactions. The numbers in the X axis correspond to patient numbers. Ta/T1 and T2/T3 represent the different stages of tumors according to TNM classification. ns not statistically significant, * statistically different p< 0.05. </p

Correlation of CYP1 enzyme activity levels with tumor stage.

<p>Group pairs were compared using Mann-U-Whitney test. Bars depict the mean values. Scatterplot depicting CYP1 activity levels in tumor samples of different TNM status and normal samples of bladder and colorectal origin. Statistical significance was set at p < 0.05. Arrows and horizontal lines indicate groups compared with statistical tests.</p

Determination of CYP1 expression by enzyme activity assay.

<p>The X axis corresponds to patient numbers while the Y axis to CYP1 activity levels. Activity was calculated from production of the metabolite luteolin per time per amount of microsomal protein. Each bar represents an average of triplicate reactions. Ta-T1 and T2-T3 correspond to different stages of tumors according to TNM. (A) Bladder samples (n=10). Colon samples (n=8). ns not statistically significant, * statistically different p< 0.05. (B) Mean CYP1 activity levels in human tumors. Bar charts indicate mean ± STDEV for bladder (n=10) and colon (n=8) tumors and normal samples. Statistical analysis was conducted using paired T test and Wilcoxon ranks test. Statistical differences were obtained for bladder and colon tumors vs normals (p<0.05). </p