The human cytochrome P450 enzymes (P450s) catalyze oxidative reactions of a broad spectrum of substrates and play a critical role in the metabolism of xenobiotics, such as drugs and dietary compounds. CYP3A4 is known to be the main enzyme involved in the metabolism of drugs and most other xenobiotics. Dietary compounds, of which polyphenolics are the most studied, have been shown to interact with CYP3A4 and alter its expression and activity. Traditionally, the liver was considered the prime site of CYP3A-mediated first-pass metabolic extraction, butin vitroandin vivostudies now suggest that the small intestine can be of equal or even greater importance for the metabolism of polyphenolics and drugs. Recent studies have pointed to the role of gut microbiota in the metabolic fate of polyphenolics in human, suggesting their involvement in the complex interactions between dietary polyphenols and CYP3A4. Last but not least, all the above suggests that coadministration of drugs and foods that are rich in polyphenols is expected to stimulate undesirable clinical consequences. This review focuses on interactions between dietary polyphenols and CYP3A4 as they relate to structural considerations, food-drug interactions, and potential negative consequences of interactions between CYP3A4 and polyphenols.

Can mutations in Cytochrome P450 3A4 (CYP3A4), the major food- and drug-metabolizing enzyme, serve as biomarkers for personalized precise medicine? Classical genetic studies provide only limited data regarding the frequencies of CYP3A4 mutations and their role in food–drug interactions. Here, in an analysis of one large database of 141,456 individuals, we found 856 SNPs (single nucleotide polymorphism), of which 312 are missense mutations, far more than the previously reported dozens. Analyzing the data further, it is demonstrated that the frequency of mutations differs among ethnic groups. Hierarchical clustering divided the mutations to seven groups, each corresponding to a specific ethnicity. To the best of our knowledge this is the first comprehensive analysis of CYP3A4 allele frequencies in distinct ethnic groups. We suggest ethnicity based classification of CYP3A4 SNPs as the first step toward precise diet and medicine. Understanding which and when polymorphism might have clinical significance is a tremendously complex task. Using modeling approach, we could predict changes in the binding poses of ligands in the active site of single variants. These changes might imply clinical effects of the overlooked protein-altering CYP3A4 mutations, by modifying drug metabolism and FDI. It may be concluded that dietary habits, and hence FDI, are matters of ethnicity. Consequently, ethnic-related polymorphism in CYP3A4 and diet may be one underlying mechanism of response to medical regimes. The approaches presented here have the power to highlight mutations of clinical relevance in any gene of interest, thus to complement the arsenal of classic genetic screening tools.

The activity of a new, terpene-based formulation, code-named NT-VRL-1, against Human Coronavirus (HCoV) strain 229E was evaluated in human lung fibroblasts (MRC-5 cells), with and without the addition of cannabidiol (CBD). The main constituents in the terpene formulation used for the experiment were beta caryophyllene, eucalyptol, and citral. The tested formulation exhibited an antiviral effect when it was pre-incubated with the host cells prior to virus infection. The combination of NT-VRL-1 with CBD potentiated the antiviral effect better than the positive controls pyrazofurin and glycyrrhizin. There was a strong correlation between the quantitative results from a cell-viability assay and the cytopathic effect seen under the microscope after 72 h. To the best of our knowledge, this is the first report of activity of a combination of terpenes and CBD against a coronavirus.

Climate change has been shown to have a substantial impact on agriculture and high temperatures and heat stress are known to have many negative effects on the vegetative and reproductive phases of plants. In a previous study, we addressed the effects of high temperature environments on olive oil yield and quality, by comparing the fruit development and oil accumulation and quality of five olive cultivars placed in high temperature and moderate temperature environments. The aim of the current study was to explore the molecular mechanism resulting in the negative effect of a high temperature environment on oil quantity and quality. We analyzed the transcriptome of two extreme cultivars, ‘Barnea’, which is tolerant to high temperatures in regard to quantity of oil production, but sensitive regarding its quality, and ‘Souri’, which is heat sensitive regarding quantity of oil produced, but relatively tolerant regarding its quality. Transcriptome analyses have been carried out at three different time points during fruit development, focusing on the genes involved in the oil biosynthesis pathway. We found that heat-shock protein expression was induced by the high temperature environment, but the degree of induction was cultivar dependent. The ‘Barnea’ cultivar, whose oil production showed greater tolerance to high temperatures, exhibited a larger degree of induction than the heat sensitive ‘Souri’. On the other hand, many genes involved in olive oil biosynthesis were found to be repressed as a response to high temperatures. OePDCT as well as OeFAD2 genes showed cultivar dependent expression patterns according to their heat tolerance characteristics. The transcription factors OeDof4.3, OeWRI1.1, OeDof4.4 and OeWRI1.2 were identified as key factors in regulating the oil biosynthesis pathway in response to heat stress, based on their co-expression characteristics with other genes involved in this pathway. Our results may contribute to identifying or developing a more heat tolerant cultivar, which will be able to produce high yield and quality oil in a future characterized by global warming.

CYP3A4 is the main human enzyme responsible for phase I metabolism of dietary compounds, prescribed drugs and xenobiotics, steroid hormones, and bile acids. The inhibition of CYP3A4 activity might impair physiological mechanisms, including the endocrine system and response to drug admission. Here, we aimed to discover new CYP3A4 inhibitors from food and dietary supplements. A deep-learning model was built that classifies compounds as either an inhibitor or noninhibitor, with a high specificity of 0.997. We used this classifier to virtually screen ∼60,000 dietary compounds. Of the 115 identified potential inhibitors, only 31 were previously suggested. Many herbals, as predicted here, might cause impaired metabolism of drugs, and endogenous hormones and bile acids. Additionally, by applying Lipinski’s rules of five, 17 compounds were also classified as potential intestine local inhibitors. New CYP3A4 inhibitors predicted by the model, bilobetin and picropodophyllin, were assayed in vitro.