Aims: This study aimed to investigate the effects of consuming Phoenix dactylifera and fasting on the mRNA expression of major hepatic drug-metabolizing enzymes in mice. Methods: Phoenix dactylifera ethanolic extract was analyzed using LC-MS/MS. We used forty-two male Balb/c mice which were treated with low (300 mg/kg) and high (2583 mg/kg) doses of Phoenix dactylifera and fasted for 24 hours, two weeks, and one month. Then, we analyzed the expression of cyp3a11, cyp2c29, cyp2d9, and ugt2b1 using real-time polymerase chain reaction assay. In addition, we assessed the relative liver weights of the mice and the hepatic phathohistological alterations. Results: We found that Phoenix dactylifera ethanolic extract contained 38 phytochemical compounds mainly kaempherol, campesterol, lutein, apigenin, genistein, and isoquercetin. Fasting significantly upregulated the mRNA expression of several drug-metabolizing enzymes in a time-dependent manner and we showed that consuming the low dose of Phoenix dactylifera significantly upregulated the expression of drug-metabolizing enzymes more than the high dose. The results of the histological examinations and relative liver weight showed that fasting and consuming of Phoenix dactylifera did not cause any toxicological alterations in the liver of the mice. Conclusion: It is concluded from this study that fasting and consuming of Phoenix dactylifera upregulated the mRNA expression of major drug-metabolizing enzymes in mouse livers. These findings may explain, at least partly, the variation of drug response during fasting of the month of Ramadan and would direct future clinical studies in optimizing dosing of pharmacotherapeutic regimen.

Objectives Phase II drug metabolism is poorly studied in advanced age and older adults may exhibit significant variability in their expression of phase II enzymes. We hypothesized that age-related changes to epigenetic regulation of genes involved in phase II drug metabolism may contribute to these effects. MethodsWe examined published epigenome-wide studies of human blood and identified the SULT1A1 and UGT1A6 genes as the top loci showing epigenetic changes with age. To assess possible functional alterations with age in the liver, we assayed DNA methylation (5mC) and histone acetylation changes around the mouse homologs Sult1a1 and Ugt1a6 in liver tissue from mice aged 4-32 months. ResultsOur sample shows a significant loss of 5mC at Sult1a1 (β = −1.08, 95% CI [−1.8, −0.2], SE = 0.38, P = 0.011), mirroring the loss of 5mC with age observed in human blood DNA at the same locus. We also detected increased histone 3 lysine 9 acetylation (H3K9ac) with age at Sult1a1 (β = 0.11, 95% CI [0.002, 0.22], SE = 0.05, P = 0.04), but no change to histone 3 lysine 27 acetylation (H3K27ac). Sult1a1 gene expression is significantly positively associated with H3K9ac levels, accounting for 23% of the variation in expression. We did not detect any significant effects at Ugt1a6. Conclusions Sult1a1 expression is under epigenetic influence in normal aging and this influence is more pronounced for H3K9ac than DNA methylation or H3K27ac in this study. More generally, our findings support the relevance of epigenetics in regulating key drug-metabolizing pathways. In the future, epigenetic biomarkers could prove useful to inform dosing in older adults.

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Background: Glucuronidation is one of the most important phase II metabolic pathways. It is catalyzed by a family of UDP-glucuronosyltransferase enzymes (UGTs). UGT1A1 and UGT1A7 catalyze the glucuronidation of a diverse range of medications, environmental chemicals and endogenous compounds. Polymorphisms in the UGT1A gene could potentially be significant for the pharmacological, toxicological and physiological effects of the enzymes. Objective: The UGT1A gene is polymorphic among ethnic groups and the aim of this study was to investigate the different UGT1A1 and UGT1A7 polymorphisms in Circassians, Chechens and Jordanian-Arabs. Method: A total of 168 healthy Jordanian-Arabs, 56 Circassians and 54 Chechens were included in this study. Genotyping of 20 different Single-nucleotide polymorphism (SNPs) was done by using polymerase chain reaction- DNA sequencing. Results: We found that Circassians and Chechens have significantly higher allele frequencies of UGT1A7*2, UGT1A7*3 and UGT1A7*4 than the Jordanian-Arab population, but all three populations have similar frequencies of UGT1A1*28. Therefore, Circassians and Chechens are expected to have significantly lower levels of the UGT1A7 enzyme with almost 90% of these populations having genes that encode low or intermediate enzyme activity. Conclusion: This inter-ethnic variation in the UGT1A alleles frequencies may affect drug response and susceptibility to cancers among different subethnic groups in Jordan. Our results can also provide useful information for the Jordanian population and for future genotyping of Circassian and Chechen populations in general.