Dose of Phenobarbital and Age of Treatment at Early Life are Two Key Factors for the Persistent Induction of Cytochrome P450 Enzymes in Adult Mouse Liver

Tien, Yun-Chen; Liu, Ke; Pope, Chad; Wang, Pengcheng; Ma, Xiaochao; Zhong, Xiao‐bo

doi:10.1124/dmd.115.066316

Cited by 29 publications

(31 citation statements)

References 44 publications

(55 reference statements)

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“…In our own study, mice treated with less than 100 mg/kg of phenobarbital at the neonatal age do not display persistent induction of CYP2B10, CYP2C29, or CYP3A11 through adult life. Only neonatal mice that were administered a dose of phenobarbital greater than this exhibited the persistent elevation of these P450 enzymes in their livers throughout life [35]. Our study also demonstrated that age is another key factor for persistent induction of P450 expression in adult mouse liver.…”

Section: Neonatal Exposure To Xenobiotics Alters P450 Expression and supporting

confidence: 53%

“…Adult male rats treated with diethylstilbestrol, a synthetic estrogen, at the neonatal age showed significant elevation in specifically CYP2C6 hepatic protein level, while rats administered phenobarbital show specific increases in CYP2C7 and CYP2B hepatic protein levels, indicating these drugs have the ability to alter the expression of certain P450 isoforms, rather than drug metabolism activity as a whole [28–30]. Phenobarbital has been the most commonly utilized drug to observe this phenomenon, and the persistent induction of CYP3A, 2B, 2C in rats and mice following early life exposure has been demonstrated numerous times [27, 28, 30–35]. Neonatal administration of lindane, an organochlorine used for lice treatment, to rats also produced an increase in the expression of CYP2B protein, along with CYP1A, later in life [36], indicating different compounds may set certain P450 levels through similar mechanisms early in life.…”

Section: Neonatal Exposure To Xenobiotics Alters P450 Expression and mentioning

confidence: 99%

“…There is a sensitive age window early in life that allows induction of P450 expression to persist after drug treatment. If drug treatment occurred beyond this window, the persistent induction was no longer evident [35]. …”

Section: Neonatal Exposure To Xenobiotics Alters P450 Expression and mentioning

confidence: 99%

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Impact of Drug Treatment at Neonatal Ages on Variability of Drug Metabolism and Drug-Drug Interactions in Adult Life

et al. 2017

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Purpose of review As the number of patients taking more than one medication concurrently continues to increase, predicting and preventing drug-drug interactions (DDIs) is now more important than ever. Administration of one drug can cause changes in the expression and activity of drug metabolizing enzymes (DMEs) and alter the efficacy or toxicity of other medications that are substrates for these enzymes, resulting in a DDI. In today’s medical practice, potential DDIs are evaluated based on the current medications a patient is taking with little regard to drugs the patient has been exposed to in the past. The purpose of this review is to discuss potential impacts of drug treatment at neonatal ages on the variability of drug metabolism and DDIs in adult life. Recent findings Existing evidence from the last thirty years has shown that exposure to certain xenobiotics during neonatal life has the potential to persistently alter DME expression through adult life. With recent advancements in the understanding of epigenetic regulation on gene expression, this phenomenon is resurfacing in the scientific community in hopes of defining possible mechanisms. Exposure to compounds that have the ability to bind nuclear receptors and trigger epigenetic modifications at neonatal and pediatric ages may have long-term, if not permanent, consequences on gene expression and DME activity. Summary The information summarized in this review should challenge the way current healthcare providers assess DDI potential and may offer an explanation to the significant interindividual variability in drug metabolism that is observed among patients.

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Section: Neonatal Exposure To Xenobiotics Alters P450 Expression and supporting

confidence: 53%

Section: Neonatal Exposure To Xenobiotics Alters P450 Expression and mentioning

confidence: 99%

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Impact of Drug Treatment at Neonatal Ages on Variability of Drug Metabolism and Drug-Drug Interactions in Adult Life

et al. 2017

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“…In this talk, we reported that the dose of drug and age of treatment in early life are two key factors for the persistent induction of gene expression and consequent increases of enzyme activities of several P450 genes in Cyp2b, Cyp2c, and Cyp3a subfamilies in adult mouse liver (Tien et al, 2015). When mice mature under normal conditions (no drug treatment in early life), their P450 expression follows the typical ontogenic pattern with increased expression with age (Peng et al, 2012).…”

Section: Effects Of Drug Treatment At Early Life On Interindividualmentioning

confidence: 99%

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Tracy¹,

Chaudhry²,

Prasad³

et al. 2015

Drug Metabolism and Disposition

151

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The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity as a result of drug-drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial interindividual variation in basal expression and/or activity, leading to differences in the rates of drug elimination and response. This interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microRNA that affect P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early postnatal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine interindividual variation are limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This article describes recent work evaluating the effect of some of these factors on interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.

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“…Recombinant human CYPs and human liver microsomes (HLM) were purchased from XenoTech (Lenexa, KS). Mouse liver microsomes (MLM) were prepared from the liver of wild-type and Cyp3a-null mice according to the previously established methods (13). Methoxylamine and NADPH were purchased from Sigma-Aldrich (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Biotransformation of Cobicistat: Metabolic Pathways and Enzymes

Wang¹,

Shehu²,

Liu³

et al. 2016

DML

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Background Cobicistat (COBI) is a pharmacoenhancer for antiretroviral therapy. Objective The current study was designed to profile the metabolic pathways of COBI and to determine the enzymes that contribute to COBI metabolism. Method We screened COBI metabolites in mice and human liver microsomes. We also used cDNA-expressed human cytochromes P450 (CYPs) to explore the role of human enzymes in COBI metabolism. Results Twenty new and three known metabolites of COBI were identified in mouse urine and feces. These new metabolic pathways of COBI include glycine conjugation, N-acetyl cysteine conjugation, morpholine ring-opening, and thiazole ring-opening. Twelve of COBI metabolites were further confirmed in mouse and human liver microsomes, including nine new metabolites. Consistent with the previous report, CYP3A4 and CYP2D6 were determined as the major enzymes that contribute to COBI metabolism. Conclusion This study provided a full map of COBI metabolism. These results can be used to manage CYP-mediated drug-drug interactions and adverse drug reactions that are associated with COBI-containing regimens in human.

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Dose of Phenobarbital and Age of Treatment at Early Life are Two Key Factors for the Persistent Induction of Cytochrome P450 Enzymes in Adult Mouse Liver

Cited by 29 publications

References 44 publications

Impact of Drug Treatment at Neonatal Ages on Variability of Drug Metabolism and Drug-Drug Interactions in Adult Life

Impact of Drug Treatment at Neonatal Ages on Variability of Drug Metabolism and Drug-Drug Interactions in Adult Life

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Biotransformation of Cobicistat: Metabolic Pathways and Enzymes

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