Ambient tonicity and intestinal cytochrome CYP3A

Chuang, Andrew I.; Itô, Shinya

doi:10.1517/17425251003781912

Cited by 4 publications

(3 citation statements)

References 98 publications

(83 reference statements)

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“…B) in db/db mice. In vitro studies have shown that hypertonicity of ambient osmotic environment in cultured intestinal human cells increases expression of CYP3A (Chuang and Ito ). Furthermore, after spontaneous ingestion of solid food with free access to water, rodent intestinal osmolality may reach 600–800 mOsm kg −1 , which is at least a twofold increase compared with the measured plasma osmolality of 300 mOsm kg −1 (Osaka et al.…”

Section: Resultsmentioning

confidence: 99%

Modulation of CYP3a expression and activity in mice models of type 1 and type 2 diabetes

Patoine

Petit

Pilote

et al. 2014

Pharmacology Res & Perspec

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CYP3A4, the most abundant cytochrome P450 enzyme in the human liver and small intestine, is responsible for the metabolism of about 50% of all marketed drugs. Numerous pathophysiological factors, such as diabetes and obesity, were shown to affect CYP3A activity. Evidences suggest that drug disposition is altered in type 1 (T1D) and type 2 diabetes (T2D). The objective was to evaluate the effect of T1D and T2D on hepatic and intestinal CYP3a drug-metabolizing activity/expression in mice. Hepatic and intestinal microsomes were prepared from streptozotocin-induced T1D, db/db T2D and control mice. Domperidone was selected as a probe substrate for CYP3a and formation of five of its metabolites was evaluated using high performance liquid chromatography. Hepatic CYP3a protein and mRNA expression were assessed by Western blot and reverse-transcription quantitative polymerase chain reaction respectively. Hepatic microsomal CYP3a activity was significantly increased in both T1D and T2D groups versus control group. Intestinal CYP3a activity was also significantly increased in both T1D and T2D groups. Moreover, significant increases of both hepatic CYP3a mRNAs and protein expression were observed in both T1D and T2D groups versus control group. Additional experiments with testosterone further validated the increased activity of CYP3a under the effect of both T1D and T2D. Although differences exist in the pathophysiological insults associated with T1D and T2D, our results suggest that these two distinct diseases may have the same modulating effect on the regulation of CYP3a, ultimately leading to variability in drug response, ranging from lack of effect to life-threatening toxicity.

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Section: Resultsmentioning

confidence: 99%

Modulation of CYP3a expression and activity in mice models of type 1 and type 2 diabetes

Patoine

Petit

Pilote

et al. 2014

Pharmacology Res & Perspec

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“…Nevertheless, hyper-tonicity-induced HMOX1 expression is observed under conditions in which NFAT5 is known to be activated (68). NFAT5 is a potent regulator of cytochrome P450 3A (CYP3A) family members (69). CYP proteins are heme-containing mono-oxygenases that are principally responsible for metabolizing xenobiotics and toxins.…”

Section: Hyperosmotic Stress and Adaptive Responsementioning

confidence: 99%

The role of hyperosmotic stress in inflammation and disease

Brocker

Thompson²,

Vasiliou

2012

BioMolecular Concepts

240

212

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Hyperosmotic stress is an often overlooked process that potentially contributes to a number of human diseases. Whereas renal hyperosmolarity is a well-studied phenomenon, recent research provides evidence that many non-renal tissues routinely experience hyperosmotic stress that may contribute significantly to disease initiation and progression. Moreover, a growing body of evidence implicates hyperosmotic stress as a potent inflammatory stimulus by triggering proinflammatory cytokine release and inflammation. Under physiological conditions, the urine concentrating mechanism within the inner medullary region of the mammalian kidney exposes cells to high extracellular osmolarity. As such, renal cells have developed many adaptive strategies to compensate for increased osmolarity. Hyperosmotic stress is linked to many maladies, including acute and chronic, as well as local and systemic, inflammatory disorders. Hyperosmolarity triggers cell shrinkage, oxidative stress, protein carbonylation, mitochondrial depolarization, DNA damage, and cell cycle arrest, thus rendering cells susceptible to apoptosis. However, many adaptive mechanisms exist to counter the deleterious effects of hyperosmotic stress, including cytoskeletal rearrangement and up-regulation of antioxidant enzymes, transporters, and heat shock proteins. Osmolyte synthesis is also up-regulated and many of these compounds have been shown to reduce inflammation. The cytoprotective mechanisms and associated regulatory pathways that accompany the renal response to hyperosmolarity are found in many non-renal tissues, suggesting cells are commonly confronted with hyperosmotic conditions. Osmoadaptation allows cells to survive and function under potentially cytotoxic conditions. This review covers the pathological consequences of hyperosmotic stress in relation to disease and emphasizes the importance of considering hyperosmolarity in inflammation and disease progression.

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“…Cells within the kidney (renal inner medula), the gastrointestinal tract, the cornea, the liver, intervertebral discs and joints are exposed to substantial osmolarity fluctuations even under physiological conditions (reviewed in 6 ). In addition, dietary and ambient conditions can also induce hypernatremia in sites such as the respiratory epithelium and the skin, resulting in approximate hyperosmolalities of 400 mOsm/kg 7 8 9 . Hyperosmotic stress acts as an inflammatory stimulus and is implicated in various pathophysiological conditions.…”

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confidence: 99%

TSC2 mediates hyperosmotic stress-induced inactivation of mTORC1

Plescher

Teleman

Demetriades

2015

Sci Rep

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mTOR complex 1 (mTORC1) regulates cell growth and metabolism. mTORC1 activity is regulated via integration of positive growth-promoting stimuli and negative stress stimuli. One stress cells confront in physiological and pathophysiological contexts is hyperosmotic stress. The mechanism by which hyperosmotic stress regulates mTORC1 activity is not well understood. We show here that mild hyperosmotic stress induces a rapid and reversible inactivation of mTORC1 via a mechanism involving multiple upstream signaling pathways. We find that hyperosmotic stress causes dynamic changes in TSC2 phosphorylation by upstream kinases, such as Akt, thereby recruiting TSC2 from the cytoplasm to lysosomes where it acts on Rheb, the direct activator of mTORC1. This work puts together a signaling pathway whereby hyperosmotic stress inactivates mTORC1.

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Ambient tonicity and intestinal cytochrome CYP3A

Cited by 4 publications

References 98 publications

Modulation of CYP3a expression and activity in mice models of type 1 and type 2 diabetes

Modulation of CYP3a expression and activity in mice models of type 1 and type 2 diabetes

The role of hyperosmotic stress in inflammation and disease

TSC2 mediates hyperosmotic stress-induced inactivation of mTORC1

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