RNA-Seq Quantification of Hepatic Drug Processing Genes in Germ-Free Mice

Selwyn, Felcy Pavithra; Cui, Julia Yue; Klaassen, Curtis D.

doi:10.1124/dmd.115.063545

Cited by 110 publications

(85 citation statements)

References 19 publications

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“…There are certain genes for which the mRNAs are moderately altered in livers of GF mice in a previous RNA sequencing (RNA-Seq) (Selwyn et al, 2015b), but were not altered in livers of GF mice the present study (such as Ces2a,Akr1c19,Cyp2b10,Cyp3a16,etc.). This inconsistency is likely due to different techniques used (RNA-Seq versus reversetranscription qPCR), vehicle effects, and/or statistical methods.…”

Section: Discussionmentioning

confidence: 87%

Regulation of Hepatic Drug-Metabolizing Enzymes in Germ-Free Mice by Conventionalization and Probiotics

Selwyn

Cheng

Klaassen

et al. 2015

Drug Metabolism and Disposition

112

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Little is known regarding the effect of intestinal microbiota modifiers, such as probiotics and conventionalization with exogenous bacteria, on host hepatic drug metabolism. Therefore, the goal of this study was to determine the effect of these modifiers on the expression of various drug-metabolizing enzymes of the host liver. VSL3 is a probiotic that contains eight live strains of bacteria. Five groups of mice were used: 1) conventional mice (CV), 2) conventional mice treated with VSL3 in drinking water, 3) germ-free (GF) mice, 4) GF mice treated with VSL3, and 5) GF mice exposed to the conventional environment for 2 months. All mice were 3 months old at tissue collection. GF conditions markedly downregulated the cytochrome P450 (P450) 3a gene cluster, but upregulated the Cyp4a cluster, whereas conventionalization normalized their expression to conventional levels [reverse-transcription quantitative polymerase chain reaction (qPCR) and western blot]. Changes in the Cyp3a and 4a gene expression correlated with alterations in the pregnane X receptor and peroxisome proliferator-activated receptor a-DNA binding, respectively (chromatin immunoprecipitation-qPCR). VSL3 increased each bacterial component in the large intestinal content of the CV mice, and increased these bacteria even more in GF mice, likely due to less competition for growth in the GF environment. VSL3 given to conventional mice increased the mRNAs of Cyp4v3, alcohol dehydrogenase 1, and carboxyesterase 2a, but decreased the mRNAs of multiple phase II glutathione-S-transferases. VSL3 given to germ-free mice decreased the mRNAs of UDPglucuronosyltransferases 1a9 and 2a3. In conclusion, conventionalization and VSL3 alter the expression of many drug-metabolizing enzyme s in the liver, suggesting the importance of considering "bacteria-drug" interactions for various adverse drug reactions in patients.

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Section: Discussionmentioning

confidence: 87%

Regulation of Hepatic Drug-Metabolizing Enzymes in Germ-Free Mice by Conventionalization and Probiotics

Selwyn

Cheng

Klaassen

et al. 2015

Drug Metabolism and Disposition

112

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“…Quantification of the mRNA in conventional and germ-free mice indicates that 21 drug-processing genes were increased, and 34 were decreased by the germ-free condition. Probably the most important findings are that the level of mRNA encoding Cyp3a in the germ-free mice is much lower, and the level of mRNA encoding Cyp4a is much higher in livers of germ-free mice (Selwyn et al, 2015) (Fig. 15).…”

Section: Intestinal Microbiota Affects Host Drug Metabolismmentioning

confidence: 96%

“…Comparisons of the expression of the mRNAs of these drugprocessing genes in conventional and germ-free mice have been reported (Bjorkholm et al, 2009;Toda et al, 2009;Selwyn et al, 2015). Quantification of the mRNA in conventional and germ-free mice indicates that 21 drug-processing genes were increased, and 34 were decreased by the germ-free condition.…”

Section: Intestinal Microbiota Affects Host Drug Metabolismmentioning

confidence: 99%

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Review: Mechanisms of How the Intestinal Microbiota Alters the Effects of Drugs and Bile Acids

2015

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Information on the intestinal microbiota has increased exponentially this century because of technical advancements in genomics and metabolomics. Although information on the synthesis of bile acids by the liver and their transformation to secondary bile acids by the intestinal microbiota was the first example of the importance of the intestinal microbiota in biotransforming chemicals, this review will discuss numerous examples of the mechanisms by which the intestinal microbiota alters the pharmacology and toxicology of drugs and other chemicals. More specifically, the altered pharmacology and toxicology of salicylazosulfapridine, digoxin, L-dopa, acetaminophen, caffeic acid, phosphatidyl choline, carnitine, sorivudine, irinotecan, nonsteroidal anti-inflammatory drugs, heterocyclic amines, melamine, nitrazepam, and lovastatin will be reviewed. In addition, recent data that the intestinal microbiota alters drug metabolism of the host, especially Cyp3a, as well as the significance and potential mechanisms of this phenomenon are summarized. The review will conclude with an update of bile acid research, emphasizing the bile acid receptors (FXR and TGR5) that regulate not only bile acid synthesis and transport but also energy metabolism. Recent data indicate that by altering the intestinal microbiota, either by diet or drugs, one may be able to minimize the adverse effects of the Western diet by altering the composition of bile acids in the intestine that are agonists or antagonists of FXR and TGR5. Therefore, it may be possible to consider the intestinal microbiota as another drug target.

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“…A recent study demonstrated differential expression of xenobiotic metabolism in livers of germ-free or conventionally raised mice demonstrating that microbial metabolites of tryptophan act as aryl hydrocarbon receptor (AHR) activators (Selwyn et al, 2015).…”

Section: Et Vous Excrétion?mentioning

confidence: 99%

How to Determine the Role of the Microbiome in Drug Disposition

et al. 2018

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With a paradigm shift occurring in health care towards personalized and precision medicine, understanding the numerous environmental factors that impact drug disposition is of paramount importance. The highly diverse and variant nature of the human microbiome is now recognized as a factor driving inter-individual variation in therapeutic outcomes. The purpose of this review is to provide a practical guide on methodology that can be applied to study the effects of microbes on the absorption, distribution, metabolism, and excretion of drugs. We also highlight recent examples of how these methods have been successfully applied to help build the basis for researching the intersection of microbiome and pharmacology. While in vitro and in vivo preclinical models are highlighted, these methods are also relevant in late-phase drug development or even as a part of routine after-market surveillance. These approaches will aid in filling major knowledge gaps for both current and upcoming therapeutics with the long-term goal of achieving a new type of knowledge-based medicine that integrates data on the host and the microbiome.

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RNA-Seq Quantification of Hepatic Drug Processing Genes in Germ-Free Mice

Cited by 110 publications

References 19 publications

Regulation of Hepatic Drug-Metabolizing Enzymes in Germ-Free Mice by Conventionalization and Probiotics

Regulation of Hepatic Drug-Metabolizing Enzymes in Germ-Free Mice by Conventionalization and Probiotics

Review: Mechanisms of How the Intestinal Microbiota Alters the Effects of Drugs and Bile Acids

How to Determine the Role of the Microbiome in Drug Disposition

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