Age-Specific Regulation of Drug-Processing Genes in Mouse Liver by Ligands of Xenobiotic-Sensing Transcription Factors

Li, Cindy Yanfei; Renaud, Helen J.; Klaassen, Curtis D.; Cui, Julia Yue

doi:10.1124/dmd.115.066639

Cited by 28 publications

(28 citation statements)

References 45 publications

(40 reference statements)

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“…The inducibility of other hepatic drug-processing genes utilizing direct activation of pregnane X receptor and CAR has also shown to be age dependent in mice (Li et al, 2016b). Greater fold changes in RNA expression following xenobiotic treatment are typically observed at the neonatal age.…”

Section: Discussionmentioning

confidence: 99%

Consequences of Phenytoin Exposure on Hepatic Cytochrome P450 Expression during Postnatal Liver Maturation in Mice

et al. 2018

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The induction of cytochrome P450 (P450) enzymes in response to drug treatment is a significant contributing factor to drug-drug interactions, which may reduce therapeutic efficacy and/or cause toxicity. Since most studies on P450 induction are performed in adults, enzyme induction at neonatal, infant, and adolescent ages is not well understood. Previous work defined the postnatal ontogeny of drug-metabolizing P450s in human and mouse livers; however, there are limited data on the ontogeny of the induction potential of each enzyme in response to drug treatment. Induction of P450s at the neonatal age may also cause permanent alterations in P450 expression in adults. The goal of this study was to investigate the short- and long-term effects of phenytoin treatment on mRNA and protein expressions and enzyme activities of CYP2B10, 2C29, 3A11, and 3A16 at different ages during postnatal liver maturation in mice. Induction of mRNA immediately following phenytoin treatment appeared to depend on basal expression of the enzyme at a specific age. While neonatal mice showed the greatest fold changes in CYP2B10, 2C29, and 3A11 mRNA expression following treatment, the levels of induced protein expression and enzymatic activity were much lower than that of induced levels in adults. The expression of fetal CYP3A16 was repressed by phenytoin treatment. Neonatal treatment with phenytoin did not permanently induce enzyme expression in adulthood. Taken together, our data suggest that inducibility of drug-metabolizing P450s is much lower in neonatal mice than it is in adults and neonatal induction by phenytoin is not permanent.

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Section: Discussionmentioning

confidence: 99%

Consequences of Phenytoin Exposure on Hepatic Cytochrome P450 Expression during Postnatal Liver Maturation in Mice

et al. 2018

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“…Cyp3a11 expression in mice (Li et al, 2016). qRT-PCR results showed that mRNA expression of neither Pxr nor Car increased in HFD-fed mice (Fig.…”

Section: Downloaded Frommentioning

confidence: 93%

High-Fat Diet Feeding Alters Expression of Hepatic Drug-Metabolizing Enzymes in Mice

Ning

Jeong

2017

Drug Metab Dispos

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Medical conditions accompanying obesity often require drug therapy, but whether and how obesity alters the expression of drug-metabolizing enzymes and thus drug pharmacokinetics is poorly defined. Previous studies have shown that high-fat diet (HFD) feeding and subsequent obesity in mice lead to altered expression of transcriptional regulators for cytochrome P450 CYP2D6, including hepatocyte nuclear factor 4 (HNF4, a transcriptional activator of CYP2D6) and small heterodimer partner (SHP, a transcriptional repressor of CYP2D6). The objective of this study was to examine whether diet-induced obesity alters CYP2D6 expression by modulating HNF4 and SHP expression. Male CYP2D6-humanized transgenic (Tg-CYP2D6) mice were fed with HFD or matching control diet for 18 weeks. Hepatic mRNA expression of CYP2D6 decreased to a small extent in the HFD group (by 31%), but the differences in CYP2D6 protein and activity levels in hepatic S9 fractions were found insignificant between the groups. Although hepatic SHP expression did not differ between the groups, HNF4 mRNA and protein levels decreased by ∼30% in the HFD group. Among major mouse endogenous cytochrome P450 genes, Cyp1a2 and Cyp2c37 showed significant decreases in the HFD group, whereas Cyp2e1 expression did not differ between groups. Cyp2b10 and Cyp3a11 expression was higher in the HFD group, with corresponding 2.9-fold increases in hepatic CYP3A activities in HFD-fed mice. Together, these results suggest that obesity has minimal effects on CYP2D6-mediated drug metabolism, although it modulates the expression of mouse endogenous P450s in a gene-specific manner.

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“…Many genes encoding drug-metabolizing enzymes or transporters [together called drug-processing genes (DPGs)] are highly expressed in liver. Drug-metabolizing enzymes include phase-I enzymes that perform oxidation, reduction, and hydrolysis reactions; and phase-II enzymes that catalyze various conjugation reactions (Aleksunes and Klaassen, 2012;Li et al, 2016). Uptake transporters bring various chemicals into hepatocytes for biotransformation, whereas efflux transporters export chemicals out of hepatocytes for elimination into urine or bile (Klaassen and Aleksunes, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Uptake transporters bring various chemicals into hepatocytes for biotransformation, whereas efflux transporters export chemicals out of hepatocytes for elimination into urine or bile (Klaassen and Aleksunes, 2010). The expression of DPGs is regulated by xenobiotic-sensing transcription factors such as the aryl hydrocarbon receptor, constitutive androstane receptor [(CAR)/Nr1i3], and pregnane X receptor [(PXR)/Nr1i2] (Klaassen and Slitt, 2005;Cui et al, 2009;Aleksunes and Klaassen, 2012;Cui and Klaassen, 2016;Li et al, 2016;Park et al, 2016). Activation of these transcription factors by drugs or other xenobiotics alters the expression of DPGs, which may influence the pharmacokinetics of coadministered drugs or other chemicals, resulting in drug-drug interactions or drug-food reactions.…”

Section: Introductionmentioning

confidence: 99%

Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers

Lee

Cade

et al. 2017

Drug Metab Dispos

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The gut microbiome is a novel frontier in xenobiotic metabolism. Polybrominated diphenyl ethers (PBDEs), especially BDE-47 (2, 2', 4, 4'-tetrabromodiphenyl ether) and BDE-99 (2, 2', 4, 4',5-pentabromodiphenyl ether), are among the most abundant and persistent environmental contaminants that produce a variety of toxicities. Little is known about how the gut microbiome affects the hepatic metabolism of PBDEs and the PBDE-mediated regulation of drug-processing genes (DPGs) in vivo. The goal of this study was to determine the role of gut microbiome in modulating the hepatic biotransformation of PBDEs. Nine-week-old male C57BL/6J conventional (CV) or germ-free (GF) mice were treated with vehicle, BDE-47 or BDE-99 (100 mol/kg) for 4 days. Following BDE-47 treatment, GF mice had higher levels of 5-OH-BDE-47 but lower levels of four other metabolites in liver than CV mice; whereas following BDE-99 treatment GF mice had lower levels of four minor metabolites in liver than CV mice. RNA sequencing demonstrated that the hepatic expression of DPGs was regulated by both PBDEs and enterotypes. Under basal conditions, the lack of gut microbiome upregulated the subfamily but downregulated the subfamily. Following PBDE exposure, certain DPGs were differentially regulated by PBDEs in a gut microbiome-dependent manner. Interestingly, the lack of gut microbiome augmented PBDE-mediated upregulation of many DPGs, such as Cyp1a2 and Cyp3a11 in mouse liver, which was further confirmed by targeted metabolomics. The lack of gut microbiome also augmented the Cyp3a enzyme activity in liver. In conclusion, our study has unveiled a novel interaction between gut microbiome and the hepatic biotransformation of PBDEs.

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Age-Specific Regulation of Drug-Processing Genes in Mouse Liver by Ligands of Xenobiotic-Sensing Transcription Factors

Cited by 28 publications

References 45 publications

Consequences of Phenytoin Exposure on Hepatic Cytochrome P450 Expression during Postnatal Liver Maturation in Mice

Consequences of Phenytoin Exposure on Hepatic Cytochrome P450 Expression during Postnatal Liver Maturation in Mice

High-Fat Diet Feeding Alters Expression of Hepatic Drug-Metabolizing Enzymes in Mice

Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers

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