Organotin compound DBDCT induces CYP3A suppression through NF-κB-mediated repression of PXR activity

Li, Yunlan; Lin, Na; Ji, Xiaoqing; Mai, Jiaqi; Liu, Qingshan

doi:10.1039/c8mt00361k

Cited by 10 publications

(5 citation statements)

References 39 publications

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“…Currently, there are lacking of studies on the association of Sn with in ammatory markers. Li et al found that organotin compound can activate NF-κB which could regulate the production of in ammatory mediators (Afonina et al 2017;Li et al 2019). This may indicate that Sn could cause changes in in ammatory markers through in ammatory signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Associations of multiple metals with inflammatory markers in US adults: NHANES 2013-2016

Feng

Sun

Zheng

et al. 2023

Preprint

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Exposure to metals can disrupt the human immune system. However, few studies have explored the potential effects of multiple metals co-exposure on immune function related to inflammation markers in human. This study examined the associations between metals exposure and inflammatory markers.The Data were gathered from the 2013–2016 period of National Health and Nutrition Examination Survey (NHANES). Inflammatory markers included platelet count (PLT), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), the ratios of MPV to PLT (MPVP), white blood cell (WBC), and neutrophil-to-lymphocyte ratio (NLR). Associations between 13 urinary metals and inflammatory markers were estimated. Generalized linear model showed urinary barium, cadmium, lead, thallium and cobalt concentrations were associated with MPV, PLR, and NLR. In quantile g-computation, urinary metal mixture was negatively associated with MPV, but positively associated with PLR and NLR. Overall, our study demonstrated that metal mixture was associated with inflammation markers including MPV, PLR, and NLR, which enhancing the inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Associations of multiple metals with inflammatory markers in US adults: NHANES 2013-2016

Feng

Sun

Zheng

et al. 2023

Preprint

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“…Alternatively, BCG immune-stimulation downregulates liver CYP3A; while HRP intervention reverses this effect in a dose-dependent manner and protect the liver's metabolic function. CYP3A is a monooxygenase primarily expressed in the liver, and oxidizes and metabolizes more than half of the drugs used clinically [8]. Changes in its metabolic activity determine the blood concentration of the metabolized drug in the body, causing drug interactions or drug toxicity reactions, thereby directly affecting the treatment effect [9].…”

Section: Discussionmentioning

confidence: 99%

“…Relatively few studies have focused on the changes in metabolic enzymes and the associated regulatory mechanisms in viral hepatitis [6,7]. Cytochrome P450 3A (CYP3A) is a predominant human liver monooxygenase responsible for metabolizing more than half of the drugs in use today [8]. Inflammatory stimuli and viral infections downregulate hepatic cytochrome P450 protein, which increases exposure to parent drugs by reducing their clearance and/or enhancing their bioavailability [5,9].…”

Section: Introductionmentioning

confidence: 99%

Involvement of NF-κB in the reversal of CYP3A down-regulation induced by sea buckthorn in BCG-induced rats

Liu

Wang

et al. 2020

PLoS ONE

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Previous studies reported that sea buckthorn (Hippophae rhamnoides L., Elaeagnaceae, HRP) exhibits hepatoprotective effects via its anti-inflammatory and antioxidant properties as well as its inhibitory effects on collagen synthesis. However, it is unclear whether this hepatoprotective effect is also achieved by regulating liver drug metabolism enzyme pathways. Herein, we examined the regulatory effect of HRP on cytochrome P450 3A (CYP3A) in rats with immune liver injury, and explored the molecular mechanism of its hepatoprotective effect. Rat models of immunological liver injury were induced by intravenous injections of Bacillus Calmette-Guerin (BCG; 125 mg kg-1 ; 2 wks). Specific protein levels were detected by ELISA or western blot, and CYP3A mRNA expression was detected by RT-PCR. High-performance liquid chromatography (HPLC) detected relative changes in CYP3A metabolic activity based on the rates of 1-hydroxylation of the probe drug midazolam (MDZ). BCG pretreatment (125 mg kg-1) significantly down-regulated liver CYP3A protein expression compared with the control, metabolic activity, and transcription levels while up-regulating liver NF-κB, IL-1β, TNF-α and iNOS. HRP intervention (ED 50 : 78 mg kg-1) moderately reversed NF-κB, inflammatory cytokines, and iNOS activation in a dose-dependent manner (P < 0.05), and suppressed CYP3A down-regulation (P < 0.05); thereby partially alleviating liver injury. During immune liver injury, HRP may reverse CYP3A downregulation by inhibiting NF-κB signal transduction, and protect liver function, which involves regulation of enzymes transcriptionally, translationally and post-translationally. The discovery that NF-κB is a molecular target of HRP may initiate the development and optimization of a clinical therapeutic approach to mitigate hepatitis B and other immunity-related liver diseases.

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“…Proteins p53, NF-κB, and C/EBP-LIP are involved in the repression of CYP3A4 gene activity [ 9 ]. NF-κB activation plays an important role in the suppression of CYP3A genes by disrupting the binding of the PXR–RXRα complex to DNA [ 126 ]. Cytokine-mediated downregulation of CYP3A4 during the inflammatory response via the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway is of great importance [ 10 ].…”

Section: Mechanisms Of Cyp3a Regulationmentioning

confidence: 99%

The Role of CYP3A in Health and Disease

2022

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CYP3A is an enzyme subfamily in the cytochrome P450 (CYP) superfamily and includes isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43. CYP3A enzymes are indiscriminate toward substrates and are unique in that these enzymes metabolize both endogenous compounds and diverse xenobiotics (including drugs); almost the only common characteristic of these compounds is lipophilicity and a relatively large molecular weight. CYP3A enzymes are widely expressed in human organs and tissues, and consequences of these enzymes’ activities play a major role both in normal regulation of physiological levels of endogenous compounds and in various pathological conditions. This review addresses these aspects of regulation of CYP3A enzymes under physiological conditions and their involvement in the initiation and progression of diseases.

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Organotin compound DBDCT induces CYP3A suppression through NF-κB-mediated repression of PXR activity

Abstract: Organotin anticancer agent di-n-butyl-di-(4-chlorobenzohydroxamato)tin(iv) (DBDCT) exerted an inhibitory effect on its major metabolic enzyme cytochrome CYP3A.

Cited by 10 publications

References 39 publications

Associations of multiple metals with inflammatory markers in US adults: NHANES 2013-2016

Associations of multiple metals with inflammatory markers in US adults: NHANES 2013-2016

Involvement of NF-κB in the reversal of CYP3A down-regulation induced by sea buckthorn in BCG-induced rats

The Role of CYP3A in Health and Disease

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