Changes in expression of hepatic cytochrome P450 subfamily enzymes during development of adjuvant-induced arthritis in rats

Sanada, Hisakazu; Sekimoto, Miho; Kamoshita, Ayaka; Degawa, Masakuni

doi:10.2131/jts.36.181

Cited by 28 publications

(29 citation statements)

References 32 publications

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“…2. The decreases in the gene expression levels and activities of these enzymes were closely correlated with increases in the expression levels of the inflammatory cytokines, TNF-a, IL-1 and IL-6 (Sanada et al, 2011). 3.…”

Section: Nonclinical Evidence For Proinflammatory Cytokinesmentioning

confidence: 83%

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Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

Shah¹,

2014

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Phenoconversion transiently converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, potentially with corresponding changes in clinical response. This phenomenon, typically resulting from coadministration of medications that inhibit certain drug metabolizing enzymes (DMEs), is especially well documented for enzymes of the cytochrome P450 family. Nonclinical evidence gathered over the last two decades also strongly implicates elevated levels of some proinflammatory cytokines, released during inflammation, in down-regulation of drug metabolism, especially by certain DMEs of the P450 family, thereby potentially causing transient phenoconversion. Clinically, phenoconversion of NAT2, CYP2C19, and CYP2D6 has been documented in inflammatory conditions associated with elevated cytokines, such as human immunodeficiency virus infection, cancer, and liver disease. The potential of other inflammatory conditions to cause phenoconversion has not been studied but experimental and anecdotal clinical evidence supports infectioninduced down-regulation of CYP1A2, CYP3A4, and CYP2C9 as well. Collectively, the evidence supports a hypothesis that certain inflammatory conditions associated with elevated proinflammatory cytokines may cause phenoconversion of certain DMEs. Since inflammatory conditions associated with elevated levels of proinflammatory cytokines are highly prevalent, phenoconversion of genotypic EM patients into transient phenotypic PMs may be more frequent than appreciated. Since drug pharmacokinetics, and therefore the clinical response, is influenced by DME phenotype rather than genotype per se, phenoconversion (whatever its cause) can have a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies. There is a risk that focusing on genotype alone may miss important associations between clinical outcomes and DME phenotypes, thus compromising future prospects of personalized medicine.

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Section: Nonclinical Evidence For Proinflammatory Cytokinesmentioning

confidence: 83%

“…Significant decrease has been reported in gene expression levels and enzyme activities of hepatic CYP3A and CYP2B subfamily enzymes in an animal model of rheumatoid arthritis (Sanada et al, 2011). 2.…”

Section: Nonclinical Evidence For Proinflammatory Cytokinesmentioning

confidence: 99%

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

Shah¹,

2014

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“…Disease states, such as bacterial infection, 31) rheumatoid arthritis, 32) and cancer, 33) lead to fluctuations in Cyp gene expressions and the enzyme activities of their products. Here we sought to examine the mechanisms underlying the fluctuations in Cyp gene expressions under an inflammatory physiological state, using LPS-treated mice as a model of inflammation.…”

Section: Discussionmentioning

confidence: 99%

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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“…In uenza virus vaccination down regulate CYP 1A2 expression (29). In human immunode ciency virus-positive patients CYP 2D6 expression was also decreased (53).Some liver enzyme activities as CYP 2E1 and CYP 4A, alcohol dehydrogenase and N-acetyltransferase were even found to be increased (54) and some subfamily (CYP 2B and 3A) to be decreased (55) in AA or LPS treated rats. LPS treatment induced renal CYP 4A mRNAs in mice and rats (thus increased the levels of ω-hydroxylated products of fatty acids) and hepatic CYP4A in rats only (56,57).…”

Section: Which Cyp Isoforms Are More a Ected After Immune Stimulation?mentioning

confidence: 99%

Immune system - drug metabolism interactions: Toxicological insight

Yanev

2014

Adipobiology

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From many years the in ammation is considered as one important determinant of susceptibility to intoxication by xenobiotic exposure. In ammation and vaccination in most cases are connected with immune system stimulation and release of cytokines, adipokines, reactive oxygen species, nitric oxide, proteases, and lipid metabolites. That was accompanied by di erent extend of down-regulation of the main xenobiotic/drug metabolizing enzyme system cytochrome P450 (CYP) both in the liver and the adipose tissue. We need more knowledge of possible changes in the pharmacokinetics respectively in e ectiveness and side e ects of drugs used in chronically ill patients in case of occurrence of acute viral or bacterial infection in them or after the application of di erent vaccines. This would contribute signi cantly to the optimization of personal drug therapy avoiding toxicity or lack of e ectiveness. Here we tried to summarize some of the main experimental and clinical data of altered drug metabolizing enzyme system in the case of changes in the immune system due to in ammation or vaccination. 2014; 6: 31-36 Adipobiology

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Changes in expression of hepatic cytochrome P450 subfamily enzymes during development of adjuvant-induced arthritis in rats

Cited by 28 publications

References 32 publications

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

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

Immune system - drug metabolism interactions: Toxicological insight

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