Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain

Lewis, Susannah S.; Hutchinson, Mark R.; Zhang, Yingning; Hund, Dana K.; Maier, Steven F.; Rice, Kenner C.; Watkins, Linda R.

doi:10.1016/j.bbi.2013.01.005

Cited by 55 publications

(51 citation statements)

References 53 publications

(89 reference statements)

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“…This in silico technique has been successfully used previously to model the docking of morphine-3-glucuronide, other opioid drugs, tricyclic antidepressants, ethanol glucuronide, glucuronic acid and other compounds (Hutchinson et al, 2010a; Hutchinson et al, 2010b; Lewis et al, 2010; Lewis et al, 2013). …”

Section: Resultsmentioning

confidence: 99%

“…Given prior evidence that (+)-naloxone altered the predicted in silico docking of other glucuronide molecules and successfully blocked HEK-TLR4 signaling of these same molecules in vitro (Hutchinson et al, 2010b; Lewis et al, 2010; Lewis et al, 2013), we hypothesized that CortG, E 2 -3-G, and E 2 -17-G would dock on MD-2 such that when (+)-naloxone was already docked to MD-2, the drugs of interest would be less likely to dock. Similarly, in Experiment 1A, corticosterone and estradiol were also predicted to dock to MD-2 at similar residues to the glucuronide metabolites, and we hypothesize that this docking would also be altered by the presence of (+)-naloxone.…”

Section: Resultsmentioning

confidence: 99%

“…All doses were equimolar with the doses of glucuronide metabolites (morphine-3-glucuronide, ethyl glucuronide and glucuronic acid) that were sufficient to cause allodynia in prior studies (Lewis et al, 2010; Lewis et al, 2013). Corticosterone was given at a dose of 0.56 μg and CortG was given at a dose of 0.85 μg.…”

Section: Methodsmentioning

confidence: 99%

“…Specifically, morphine-3-glucuronide, ethyl-β-D-glucuronide and glucuronic acid have been shown to activate the innate immune toll-like receptor 4 (TLR4) and cause TLR4-dependent enhanced pain when administered intrathecally (Lewis et al, 2010; Lewis et al, 2013) or systemically (Due et al, 2012). Another major class of molecules with glucuronidated metabolites is the steroid hormones.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Select steroid hormone glucuronide metabolites can cause toll-like receptor 4 activation and enhanced pain

Lewis¹,

Hutchinson²,

Frick³

et al. 2015

Brain, Behavior, and Immunity

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We have recently shown that several classes of glucuronide metabolites, including the morphine metabolite morphine-3-glucuronide and the ethanol metabolite ethyl glucuronide, cause toll like receptor 4 (TLR4)-dependent signalling in vitro and enhanced pain in vivo. Steroid hormones, including estrogens and corticosterone, are also metabolized through glucuronidation. Here we demonstrate that in silico docking predicts that corticosterone, corticosterone-21-glucuronide, estradiol, estradiol-3-glucuronide and estradiol-17-glucuronide all dock with the MD-2 component of the TLR4 receptor complex. In addition to each docking with MD-2, the docking of each was altered by pre-docking with (+)-naloxone, a TLR4 signaling inhibitor. As agonist versus antagonist activity cannot be determined from these in silico interactions, an in vitro study was undertaken to clarify which of these compounds can act in an agonist fashion. Studies using a cell line transfected with TLR4, necessary co-signaling molecules, and a reporter gene revealed that only estradiol-3-glucuronide and estradiol-17-glucuronide increased reporter gene product, indicative of TLR4 agonism. Finally, in in vivo studies, each of the 5 drugs was injected intrathecally at equimolar doses. In keeping with the in vitro results, only estradiol-3-glucuronide and estradiol-17-glucuronide caused enhanced pain. For both compounds, pain enhancement was blocked by the TLR4 antagonist lipopolysaccharide from Rhodobacter sphaeroides, evidence for the involvement in TLR4 in the resultant pain enhancement. These findings have implications for several chronic pain conditions, including migraine and tempromandibular joint disorder, in which pain episodes are more likely in cycling females when estradiol is decreasing and estradiol metabolites are at their highest.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Select steroid hormone glucuronide metabolites can cause toll-like receptor 4 activation and enhanced pain

Lewis¹,

Hutchinson²,

Frick³

et al. 2015

Brain, Behavior, and Immunity

Self Cite

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“…13 Sugar acids, including glucuronic acid, are used ubiquitously in detergent and food industries, as well as in the manufacture of pharmaceutics and cosmetics. 14,15 The medicinal utility of glucuronic acid includes constructing CT DNA intercalator, 16,17 constituting a natural heparin-like compound having low anticoagulant activity, 18 and preparing antitumoral delivery systems for anticancer therapy, in particular. [19][20][21][22][23][24][25] Docking aTIQcTPc into the active pocket of P-selectin 26 In the docking investigation, P-selectin's structure was treated as a rigid one and produced with AutoDockTools 1.5, ie, merging the nonpolar hydrogens and assigning the charges of Gasteiger and the elements of AutoDock 4.…”

Section: Introductionmentioning

confidence: 99%

ATIQCTPC: a nanomedicine capable of targeting tumor and blocking thrombosis in vivo

Wang

et al. 2017

IJN

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To overcome the harmful side effects, low tolerance, and undesirable outcomes of the anticancer drugs, we used ethane-1,2-diamine to bridge antitumoral ( S )-3-acetyl-4-oxo-tetrahydroindolo[2,3-a]quinolizine-6-carboxylic acid (ATIQC) and tumor-targeting d -glucuronic acid, thereby providing (6 S )-3-acetyl-4-oxo- N -(2-(3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxamido)ethyl)-4,6,7,12-tetrahydroindolo[2,3-a]quinolizine-6-carboxamide (ATIQCTPC). Atomic force microscopy images visualized, that in serum, ATIQCTPC formed particles of height <81 nm. These particles effectively avoided phagocytosis of macrophages and were stable in blood circulation. Distribution analysis indicated that ATIQCTPC accumulated and released ATIQC in the tumor tissue through a targeting manner. Thus, the antitumor and the anti-thrombotic activities of ATIQCTPC were 100-fold higher than those of ATIQC, and ATIQCTPC was able to prevent cancer patients from suffering from thrombosis. Based on the observation that ATIQCTPC decreased serum tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) in S180 mice, we hypothesized that this is the mechanism that ATIQCTPC utilized to slow tumor growth. Additionally, we observed that ATIQCTPC inhibited thrombosis by decreasing serum P-selectin of thrombotic rats. The intermolecular association and the hexamerization manner of ATIQCTPC were experimentally evidenced and correlated with the formation of the nanoparticles.

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Uncovering the impact of alcohol on internal organs and reproductive health: Exploring TLR4/NF‐kB and CYP2E1/ROS/Nrf2 pathways

Kong,

Subramaniyan,

Lubau

2024

Anim Models and Exp Med

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This review delves into the detrimental impact of alcohol consumption on internal organs and reproductive health, elucidating the underlying mechanisms involving the Toll‐like receptor 4 (TLR4)/Nuclear factor kappa light chain enhancer of activated B cells (NF‐kB) pathway and the Cytochrome P450 2E1 (CYP2E1)/reactive oxygen species (ROS)/nuclear factor erythroid 2‐related factor 2 (Nrf2) pathways. The TLR4/NF‐kB pathway, crucial for inflammatory and immune responses, triggers the production of pro‐inflammatory agents and type‐1 interferon, disrupting the balance between inflammatory and antioxidant responses when tissues are chronically exposed to alcohol. Alcohol‐induced dysbiosis in gut microbes heightens gut wall permeability to pathogen‐associated molecular patterns (PAMPs), leading to liver cell infection and subsequent inflammation. Concurrently, CYP2E1‐mediated alcohol metabolism generates ROS, causing oxidative stress and damaging cells, lipids, proteins, and deoxyribonucleic acid (DNA). To counteract this inflammatory imbalance, Nrf2 regulates gene expression, inhibiting inflammatory progression and promoting antioxidant responses. Excessive alcohol intake results in elevated liver enzymes (ADH, CYP2E1, and catalase), ROS, NADH, acetaldehyde, and acetate, leading to damage in vital organs such as the heart, brain, and lungs. Moreover, alcohol negatively affects reproductive health by inhibiting the hypothalamic–pituitary‐gonadal axis, causing infertility in both men and women. These findings underscore the profound health concerns associated with alcohol‐induced damage, emphasizing the need for public awareness regarding the intricate interplay between immune responses and the multi‐organ impacts of alcohol consumption.

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Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain

Cited by 55 publications

References 53 publications

Select steroid hormone glucuronide metabolites can cause toll-like receptor 4 activation and enhanced pain

Select steroid hormone glucuronide metabolites can cause toll-like receptor 4 activation and enhanced pain

ATIQCTPC: a nanomedicine capable of targeting tumor and blocking thrombosis in vivo

Uncovering the impact of alcohol on internal organs and reproductive health: Exploring TLR4/NF‐kB and CYP2E1/ROS/Nrf2 pathways

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