Impact of Infectious and Inflammatory Disease on Cytochrome P450–Mediated Drug Metabolism and Pharmacokinetics

Morgan, Edward T.

doi:10.1038/clpt.2008.302

Cited by 400 publications

(371 citation statements)

References 34 publications

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“…Testosterone hydroxylation activity as indicator of CYP2B, CYP2C and CYP3A activities was markedly decreased and this decrease was associated with a decrease in total P450 content in rat hepatic microsomes, suggesting a down-regulation of CYP enzymes by LPS treatment. This CYP downregulation by LPS has been reported elsewhere (Morgan, 2009). The major causes of CYP down-regulation are the transcriptional suppression of CYP enzymes and oxidative stress, since transcriptional suppression was alleviated or blocked by the concomitant use of curcumin, an antioxidant (Sompamit et al, 2009).…”

Section: Discussionsupporting

confidence: 76%

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity

et al. 2012

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-Diclofenac (DCF), a nonsteroidal anti-inflammatory drug, is well known to induce idiosyncratic hepatotoxicity. Although there remains much to be elucidated about its onset mechanism, it is widely accepted as a hypothesis that idiosyncratic hepatotoxicity arises from a specific immune response to a hapten formed by covalent binding of drugs or their reactive metabolites to hepatic tissues. In this study, we investigated the effects of covalent binding of DCF reactive metabolites to hepatic tissues using a rat model of liver injury induced by co-treatment with lipopolysaccharide (LPS) at a non-hepatotoxic dose. In studies done in vitro using hepatic microsomes prepared from rats treated with LPS alone, 4'-and 5-hydroxylation activities on DCF metabolism and adducts of reactive metabolites to dansyl glutathione (dGSH) were markedly decreased associated with a decrease in total P450 content. However, in studies done in vivo, the LPS/DCF co-treatment significantly increased adducts of 5-hydroxydiclofenac (5-OH-DCF) to rat hepatic tissues and delayed the elimination of 5-OH-DCF from plasma. Furthermore, we investigated the effects of co-treatment on hepatic GSH level in rats. A decrease of hepatic GSH was observed with the LPS/DCF co-treatment but not with LPS or DCF alone. The results suggest that covalent binding of reactive metabolites via 5-OH-DCF to hepatic tissues may play an important role in the onset of DCF-induced idiosyncratic hepatotoxicity, especially under decreased GSH conditions.

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Section: Discussionsupporting

confidence: 76%

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity

et al. 2012

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“…In particular, because many cytokines are involved in the regulation of CYP genes, and because the cytokines affect each other's expression, it is very difficult to determine which cytokine(s) regulates the expression of which CYP gene. 17) In the present study, we paid considerable attention to the inflammatory cytokines TNFα and IL-1β, because they can downregulate the expression of multiple CYP genes, [13][14][15][16] suggesting that they could be key regulators of this process. Therefore, we assessed the TNFα and IL-1β mRNA levels in mice treated with LPS plus PCN, TCPOBOP, or B(a)P. In spite of the presence of CYP inducers, LPS treatment resulted in significant increases in the TNFα and IL-1β mRNAs (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…[13][14][15][16] In most of these studies, a decrease in CYP protein expression was succeeded or accompanied by a decrease in its mRNA, implicating transcription regulation as a primary mechanism. 17) These findings also underscore the importance of understanding the transcriptional mechanisms of the CYPs.…”

mentioning

confidence: 91%

Effect of Lipopolysaccharide on the Xenobiotic-Induced Expression and Activity of Hepatic Cytochrome P450 in Mice

Moriya

Kataoka

Fujino

et al. 2012

Biological & Pharmaceutical Bulletin

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Infection-associated inflammation can alter the expression levels and functions of cytochrome P450s (CYPs). Cyp gene expression is regulated by the activation of several nuclear receptors, including pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR). These receptors can be activated by xenobiotics, including medicines. Here, to study the xenobiotic-induced fluctuations in CYP during inflammation, we examined the effect of lipopolysaccharide (LPS) treatment on the level of mRNAs encoding hepatic CYPs induced by xenobiotic-activated nuclear receptors, in mice. Both the mRNA induction of Cyp genes and the metabolic activities of CYP proteins were examined. LPS treatment caused a significant decrease in the induced expression of the mRNAs for Cyp3a11, 2c29, 2c55, and 1a2, but not for Cyp2b10. To assess the CYP enzymatic activities, CYP3A-mediated testosterone 6β-hydroxylation and the intrinsic clearance (CL int ) of nifedipine in liver microsomes were measured in mice treated with the xenobiotic pregnenolone-16alpha-carbonitrile (PCN) with or without LPS administration. Both assays revealed that the CYP3A activity, which was induced by PCN, declined significantly after LPS treatment, and this decline correlated with the Cyp3a11 mRNA level. In addition, we found that the mRNAs for interleukin (IL)-1β and tumor necrosis factor (TNF) α were increased after treatment with LPS plus xenobiotics. Our findings demonstrated that LPS treatment reduces the PXR-and AhR-mediated, and possibly CAR-mediated Cyp gene expression and further suggest that these decreases are dependent on inflammatory cytokines in the liver.

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“…Therefore, doses may be adjusted or an alternative drug may be prescribed for patients with particular highrisk genotypes or phenotypes, namely personalized or precision medicine, to achieve the desired efficacy and prevent adverse effects. Furthermore, drug-metabolizing enzyme and transporter gene expression is regulated by nuclear receptors [NRs; e.g., pregnane X receptor (PXR or NR1I2)) and transcription factors, and modulated through signal transduction, posttranslational modification, membrane trafficking and subcellular organization pathways (for reviews, see Correia and Liao, 2007;Morgan, 2009;Gu and Manautou, 2010;Klaassen and Aleksunes, 2010;Tolson and Wang, 2010)]. Activation or suppression of such regulatory factors or pathways would cause significant change in enzyme/transporter levels and activities and lead to multidrug resistance (MDR), loss of efficacy, or adverse drug effects.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA Pharmacoepigenetics: Posttranscriptional Regulation Mechanisms behind Variable Drug Disposition and Strategy to Develop More Effective Therapy

Tian

et al. 2015

Drug Metabolism and Disposition

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Knowledge of drug absorption, distribution, metabolism, and excretion (ADME) or pharmacokinetics properties is essential for drug development and safe use of medicine. Varied or altered ADME may lead to a loss of efficacy or adverse drug effects. Understanding the causes of variations in drug disposition and response has proven critical for the practice of personalized or precision medicine. The rise of noncoding microRNA (miRNA) pharmacoepigenetics and pharmacoepigenomics has come with accumulating evidence supporting the role of miRNAs in the modulation of ADME gene expression and then drug disposition and response. In this article, we review the advances in miRNA pharmacoepigenetics including the mechanistic actions of miRNAs in the modulation of Phase I and II drug-metabolizing enzymes, efflux and uptake transporters, and xenobiotic receptors or transcription factors after briefly introducing the characteristics of miRNA-mediated posttranscriptional gene regulation. Consequently, miRNAs may have significant influence on drug disposition and response. Therefore, research on miRNA pharmacoepigenetics shall not only improve mechanistic understanding of variations in pharmacotherapy but also provide novel insights into developing more effective therapeutic strategies.

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Impact of Infectious and Inflammatory Disease on Cytochrome P450–Mediated Drug Metabolism and Pharmacokinetics

Cited by 400 publications

References 34 publications

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity

Increase in covalent binding of 5-hydroxydiclofenac to hepatic tissues in rats co-treated with lipopolysaccharide and diclofenac: involvement in the onset of diclofenac-induced idiosyncratic hepatotoxicity

Effect of Lipopolysaccharide on the Xenobiotic-Induced Expression and Activity of Hepatic Cytochrome P450 in Mice

MicroRNA Pharmacoepigenetics: Posttranscriptional Regulation Mechanisms behind Variable Drug Disposition and Strategy to Develop More Effective Therapy

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