Search

1. Phase-II enzymes are important in metabolizing many xenobiotics including prescription drugs and chemical carcinogens. Whereas it is known that diet can alter the expression of phase-II conjugation enzymes, the previous studies are limited in using only two or three diets and examining only a few enzymes. 2. Adult male C57BL6 mice were fed one of nine diets for 3 weeks. Of the 87 genes encoding major hepatic phase-II enzymes, approximately one-half (43) were altered by at least one diet. Diet restriction altered the hepatic expression of the most genes encoding phase-II enzymes (27), followed by lab chow (15), atherogenic diet (13), high-fat diet (10), western diet (7), high-fructose diet (5), and essential fatty acid-deficient diet (3), whereas the low n-3 fatty acid diet had no effect on the hepatic expression of these phase-II enzymes. 3. This comprehensive study provides detailed information on which conjugation enzymes are changed by these diets, and these data can be used to further investigate the mechanism for these changes in messenger RNAs, and whether these changes result in alterations in enzyme activity and drug action.

1. Lifestyle diseases are often caused by inappropriate nutrition habits and attempted to be treated by polypharmacotherapy. Therefore, it is important to determine whether differences in diet affect the disposition of drugs. Xenobiotic transporters in the liver are essential in drug disposition. 2. In the current study, mice were fed one of nine diets for 3 weeks. The mRNAs of 23 known xenobiotic transporters in livers of mice were quantified by microarray analysis, and validated by branched DNA assay. The mRNAs of 15 transporters were altered by at least one diet. Diet-restriction (10) and the atherogenic diet (10) altered the expression of the most number of transporters, followed by western diet (8), high-fat diet (4), lab chow (2), high-fructose diet (2) and EFA-deficient diet (2), whereas the low n-3 FA diet had no effect on these transporters. Seven of the 11 xenobiotic transporters in the Slc family, three of four in the Abcb family, two of four in the Abcc family and all three in the Abcg family were changed significantly. 3. This first comprehensive study indicates that xenobiotic transporters are altered by diet, and suggests there are likely diet-drug interactions due to changes in the expression of drug transporters.

Developmental regulation of gene expression is controlled by distinct epigenetic signatures catalyzed by various epigenetic modifiers. Little is known about the ontogeny and tissue distribution of these epigenetic modifiers. In the present study, we used a novel approach of RNA-sequencing to elucidate hepatic ontogeny and tissue distribution of mRNA expression of 142 epigenetic modifiers, including enzymes involved in DNA methylation/demethylation, histone acetylation/deacetylation, histone methylation/demethylation, histone phosphorylation and chromosome remodeling factors in male C57BL/6 mice. Livers from male C57BL/6 mice were collected at 12 ages from prenatal to adulthood. Many of these epigenetic modifiers were expressed at much higher levels in perinatal livers than adult livers, such as Dnmt1, Dnmt3a, Dnmt3b, Apobec3, Kat1, Ncoa4, Setd8, Ash2l, Dot1l, Cbx1, Cbx3, Cbx5, Cbx6, Ezh2, Suz12, Eed, Suv39h1, Suv420h2, Dek, Hdac1, Hdac2, Hdac7, Kdm2b, Kdm5c, Kdm7, Prmt1–5, Prmt7, Smarca4, Smarcb1, Chd4 and Ino80e. In contrast, hepatic mRNA expression of a few epigenetic modifiers increased during postnatal liver development, such as Smarca2, Kdm1b, Cbx7 and Chd3. In adult mice (60 d of age), most epigenetic modifiers were expressed at moderately (1–3-fold) higher levels in kidney and/or small intestine than liver. In conclusion, this study, for the first time, unveils developmental changes in mRNA abundance of all major known epigenetic modifiers in mouse liver. These data suggest that ontogenic changes in mRNA expression of epigenetic modifiers may play important roles in determining the addition and/or removal of corresponding epigenetic signatures during liver development.

Drug processing genes (DPGs), namely uptake transporters, phase-I and phase-II enzymes, as well as efflux transporters are responsible for the absorption, distribution, metabolism, and excretion of xenobiotics. The constitutive and/or inducible expression of these DPGs is regulated by a group of nuclear receptors/transcription factors. There is increasing evidence that these DPGs and nuclear receptors are regulated by epigenetic mechanisms, namely DNA methylation, histone modifications, and microRNAs. Herein, we summarize the current state of knowledge of the epigenetic regulation of these DPGs and nuclear receptors, with particular emphasis on roles of epigenetics in regulating tissue-specific expression, changes in gene expression during development, and alterations of gene expression during carcinogenesis.