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The open source database "OpenCYP database" has been developed based on the results of extensive literature searches from the peer-reviewed literature. OpenCYP provides data on human variability on baseline of activities and polymophism frequencies for selected cytochrome P-450 isoforms (CYP1A2, CYP2A6, CYP2D6, CYP3A4/3A5 and CYP3A7) in healthy adult populations from world populations. CYP enzymatic activities were generally expressed as the metabolic ratio (MR) between an unchanged probe drug and its metabolite(s) in urine or plasma measured in healthy adults. Data on other age groups were very limited and fragmented, constituting an important data gap. Quantitative comparisons were often hampered by the different experimental conditions used. However, variability was quite limited for CYP1A2, using caffeine as a probe substrate, with a symmetrical distribution of metabolic activity values. For CYP3A4, human variability was dependent on the probe substrate itself with low variability when data considering the dextromethorphan/demethilathed metabolite MR were used and large variability when the urinary 6β-hydroxycortisol/cortisol ratio was used. The largest variability in CYP activity was shown for CYP2D6 activity, after oral dosing of dextromethorphan, for which genetic polymorphisms are well characterised and constitute a significant source of variability. It is foreseen that the OpenCYP database can contribute to promising tools to support the further development of QIVIVE and PBK models for human risk assessment of chemicals particularly when combined with information on isoform-specific content in cells using proteomic approaches.
The effects of interleukin (IL)-1 beta, IL-4, IL-6, tumor necrosis factor (TNF)-alpha, interferon (IFN)-alpha, IFN-gamma, and transforming growth factor (TGF)-beta 1 on cytochrome P-450 (CYP) 1A expression and polycyclic aromatic hydrocarbon (PAH)-mediated induction in primary human hepatocyte cultures were determined. Most cytokines that were previously found to decrease basal CYP expression could counteract PAH induction of CYP1A mRNA and its associated ethoxyresorufin-O-deethylation (EROD) activity. IL-1 beta and TNF-alpha blocked 3-methylcholanthrene (3-MC)-induced EROD activity by up to 25 and 44%, respectively. IFN-alpha and IFN-gamma antagonized EROD induction by up to 61 and 70%, respectively. TGF-beta 1 proved to be the most effective cytokine, because 72 hr of treatment with 2 ng/ml TGF-beta 1 produced nearly 100% inhibition of 3-MC- and benzo(a)pyrene-induced CYP1A1 and CYP1A2 mRNAs and EROD activity. Treatment with cycloheximide in combination with 3-MC led to superinduction of CYP1A mRNA, under which conditions TGF-beta 1 did not block induction, suggesting the requirement for protein synthesis for the suppressive effect of the cytokine. In addition, TGF-beta 1 augmented AP-1-binding activity, suggesting that fos and/or jun protooncogene products could be implicated in the response. Our results demonstrate that IL-1 beta, TNF-alpha, and IFNs antagonized PAH-mediated induction of CYP1A gene expression in human hepatocytes. In addition, we report the finding of a novel effect of TGF-beta 1, which was able to prevent CYP1A1 and -1A2 induction by two different PAHs.
Approximately 75% of xenobiotics are primarily eliminated through metabolism; thus the accurate scaling of metabolic clearance is vital to successful drug development. Yet, when data is scaled from in vitro to in vivo, hepatic metabolic clearance, the primary source of metabolism, is still commonly underpredicted. Over the past decades, with biophysics used as a key component to restore aspects of the in vivo environment, several new cell culture settings have been investigated to improve hepatocyte functionalities. Most of these studies have focused on shear stress, i.e., flow mediated by a pressure gradient. One potential conclusion of these studies is that hepatocytes are naturally "mechanosensitive," i.e., they respond to a change in their biophysical environment. We demonstrate that hepatocytes also respond to an increase in hydrostatic pressure that, we suggest, is directly linked to the lobule geometry and vessel density. Furthermore, we demonstrate that hydrostatic pressure improves albumin production and increases cytochrome P-450 (CYP) 1A2 expression levels in an aryl hydrocarbon-dependent manner in human hepatocytes. Increased albumin production and CYP function are commonly attributed to the impacts of shear stress in microfluidic experiments. Therefore, our results highlight evidence of a novel link between hydrostatic pressure and CYP metabolism and demonstrate that the spectrum of hepatocyte mechanosensitivity might be larger than previously thought.
The majority of insecticides currently in use throughout the world belong to the class of the organophosphorus insecticides. Many of these compounds, such as the phosphorothioate insecticides, exert their mammalian toxicity only after undergoing metabolic activation by a variety of cytochrome P450 isoforms to produce their corresponding oxygen analogs (or oxons), which are potent inhibitors of the critical enzyme acetylcholinesterase. Of the many chemicals identified that can modulate cytochrome P450-dependent activities, the flavonoids represent some of the most unusual compounds in that they have been reported to both inhibit and stimulate certain activities. The present study was undertaken to determine if representative flavonoids (at in vitro concentrations of 1-100 microM) can alter the mammalian cytochrome P450-dependent biotransformation and acute toxicity of the phosphorothioate insecticide parathion. The flavonoids 5,6-benzoflavone, flavone, and quercetin had the biphasic effect of stimulating mouse hepatic microsomal parathion oxidation at a concentration of 1 microM, and inhibiting this same activity when increased to 100 microM. In contrast, 7,8-benzoflavone was only inhibitory at all concentrations examined. All the flavonoids examined except quercetin altered the ratio of activation/detoxification of parathion by mouse hepatic microsomes, but had no effect on this same ratio with human CYP1A2. These data suggest that the changes in the activation/detoxification ratio observed with mouse hepatic microsomes resulted from selective inhibition or stimulation of various cytochrome P450 isoforms rather than a flavonoid-induced alteration in the nonenzymatic rearrangement of the putative phosphooxythirane intermediate generated by cytochromes P450 from parathion. Surprisingly, however, none of the four flavonoids in the current study affected the lethality of parathion in vivo, suggesting that the flavonoid-induced alterations in cytochrome P-450-dependent metabolism of parathion documented in vitro were simply not great enough to be of any significance in vivo.
Second-generation antipsychotic metabolism is mainly carried out by the CYP450 superfamily, which is highly polymorphic. Therefore, knowing the influence of the different known CYP450 polymorphisms on antipsychotic plasmatic levels and, consequently, the biological effect could contribute to a deeper knowledge of interindividual antipsychotic treatment variability, prompting possible solutions. Considering this, this state of the art review aimed to summarize the current knowledge about the influence of the diverse characterized phenotypes on the metabolism of the most used second-generation antipsychotics. Forty studies describing different single nucleotide polymorphisms (SNPs) associated with the genes CYP1A2, CYP2D6, CYP3A4, CYP3A5, and ABCB1 and their influence on pharmacokinetics of olanzapine, clozapine, aripiprazole, risperidone, and quetiapine. Most of the authors concluded that although significant differences in the pharmacokinetic parameters between the different phenotypes could be observed, more thorough studies describing pharmacokinetic interactions and environmental conditions, among other variables, are needed to fully comprehend these pharmacogenetic interactions.
MicroRNAs (miRNAs) that regulate the cytochrome P-450 isoforms involved in acetaminophen (APAP) toxicity were examined in HepaRG cells treated with APAP (20 mM). In-vitro studies found that APAP protein adducts were increased at 1 h, followed by ALT increases at 12 and 24 h. CYP1A2, CYP3A4 and CYP2E1 mRNA levels were decreased, while miRNAs were increased for miR-122-5p, miR-378a-5p, miR-27b-3p at 6 h and miR-125b-5p at 12 h and miR-27b-3p at 24 h. Putative miRNA binding sites on the 3'UTRs of the CYPs were identified in-silico. Overexpression of miR-122-5p and miR-378a-5p in cells suppressed protein expression of CYP1A2, CYP3A4 and CYP2E1. Luciferase reporter assays confirmed the interaction between miR-122 and the 3'UTR of the CYP1A2 and CYP3A4. Thus, the in-vitro experiments showed that miR-122-5p and miR-378a-5p upregulation were associated with translational repression of CYPs. Serum samples of children with APAP overdose had significant elevation of miR-122-5p, miR-378a-5p, miR-125b-5p and miR-27b-3p, compared to healthy controls and receiver operator curves of the miRNAs had AUCs of 91 to 100%. Collectively, the data suggest that miRNA elevations in APAP toxicity represent a regulatory response to modify CYP1A2, CYP3A4 and CYP2E1 translation due to cellular stress and injury.
Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. The present study investigated the expression of Cytochrome P-450 (CYP) genes: CYP1A2, CYP3A4 and CYP3A5 by qRT-PCR in 135 specimens obtained from OS patients, including biopsy (pre-chemotherapy), tumor resected in surgery (post-chemotherapy), adjacent bone to tumor (nonmalignant tissue), pulmonary metastasis and adjacent lung to metastasis (nonmalignant tissue). Normal bone and normal lung tissues were used as control. We also investigated in five OS cell lines the modulation of CYPs expression by cisplatin, doxorubicin and methotrexate. As result, the adjacent lung specimens presented CYP1A2 overexpression compared to the normal lung (p=0.0256). Biopsy specimens presented lower CYP3A4 expression than normal bone (p=0.0314). The overexpression of both CYP1A2 and CYP3A4 in post-chemotherapy specimens were correlated with better event free-survival (p=0.0244) and good response (p=0.0484), respectively. Furthermore, in vitro assays revealed that CYP1A2 was upregulated by doxorubicin (p=0.0034); CYP3A4 was upregulated by cisplatin, doxorubicin and methotrexate (p=0.0004, p=0.0024, p<0.0001, respectively); and CYP3A5 was downregulated by doxorubicin (p=0.0285) and upregulated in time-dependent manner by methotrexate (p=0.0239). In conclusion, our findings suggest that CYP genes play an important role in OS tumorigenesis, at primary and metastatic sites, as well in treatment response.
Primary mouse hepatocyte cultures are widely used in toxicological and pharmacological studies. However, the strain differences in alterations of metabolic enzymes and the regulation of gene expression in response to different stimuli remains unclear. To address this issue, we examined the expression of metabolic enzymes and the regulatory role of DNA methylation in the primary hepatocytes of two mouse strains, CD-1 and C57BL/6. Primary culture of mouse hepatocytes was established using collagen sandwich configuration. Analysis of gene expression of 24 phase I, 18 phase II, and 6 phase III metabolic enzymes on 4 consecutive days after cell seeding revealed that the basal levels of most enzymes in primary cultured hepatocytes differed greatly between the two mouse strains. However, the dynamic changes in most genes were identical between the two strains. In addition, treatment with 3-methylcholanthrene, phenobarbital, and rifampin led to the induction of cytochrome P-450 (cyp) 1a1 and cyp1a2, cyp2b10, cyp3a11. However, induction varied in degree between the two types of primary hepatocytes. The dynamic changes in global DNA methylation and the expression of DNA methylation regulatory factors of the two mouse strains were similar. Of the genes down-regulated over the culture period, hypermethylation of cyp2e1 gene appeared in both mouse strains and led to a suppression of gene expression. Taken together, these results demonstrate that the expression of metabolic enzymes and the response to agonists in primary hepatocytes differ between CD-1 and C57BL/6 mouse strains. Epigenetic regulation might be involved in the suppression of cyp 450s' expression.
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