Hepatic fatty acid conjugation of 2‐chloroethanol and 2‐bromoethanol in rats

Kaphalia, Bhupendra S.; Ansari, Ghulam

doi:10.1002/jbt.2570040307

Cited by 29 publications

(19 citation statements)

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“…This is further supported by the studies in laboratory animals and in vitro after ethanol exposure (Shore and Theorell, 1966; Baker et al, 1973; Zahlten et al, 1980; Sharkawi, 1984; Kaphalia et al, 1996; Ciuclan et al, 2010). On the other hand, hepatic microsomal cytochrome P450 2E1 (CYP2E1) induced after chronic ethanol exposure is advocated as an important pathway for oxidative metabolism of ethanol resulting in oxidative stress due to generation of reactive oxygen species contributing to pathogenesis of ALD (Lieber, 2004; Cederbaum, 2010).…”

Section: Introductionmentioning

confidence: 59%

Hepatic lipid profiling of deer mice fed ethanol using 1H and 31P NMR spectroscopy: A dose-dependent subchronic study

Fernando¹,

Bhopale²,

Boor³

et al. 2012

Toxicology and Applied Pharmacology

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Chronic alcohol abuse is a 2nd major cause of liver disease resulting in significant morbidity and mortality. Alcoholic liver disease (ALD) is characterized by a wide spectrum of pathologies starting from fat accumulation (steatosis) in early reversible stage to inflammation with or without fibrosis and cirrhosis in later irreversible stages. Previously, we reported significant steatosis in the livers of hepatic alcohol dehydrogenase (ADH)-deficient (ADH−) vs. hepatic ADH-normal (ADH+) deer mice fed 4% ethanol daily for 2 months [Bhopale et al., 2006, Alcohol 39, 179–188]. However, ADH− deer mice fed 4% ethanol also showed a significant mortality. Therefore, a dose-dependent study was conducted to understand the mechanism and identify lipid(s) involved in the development of ethanol-induced fatty liver. ADH− and ADH+ deer mice fed 1, 2 or 3.5% ethanol daily for 2 months and fatty infiltration in the livers were evaluated by histology and by measuring dry weights of extracted lipids. Lipid metabolomic changes in extracted lipids were determined by proton (1H) and 31phosphorus (31P) nuclear magnetic resonance (NMR) spectroscopy. The NMR data was analyzed by hierarchical clustering (HC) and principle component analyses (PCA) for pattern recognition. Extensive vacuolization by histology and significantly increased dry weights of total lipids found only in the livers of ADH− deer mice fed 3.5% ethanol vs. pair-fed controls suggest a dose-dependent formation of fatty liver in ADH− deer mouse model. Analysis of NMR data of ADH− deer mice fed 3.5% ethanol vs. pair-fed controls shows increases for total cholesterol, esterified cholesterol, fatty acid methyl esters (FAMEs), triacylglycerides and unsaturation, and decreases for free cholesterol, phospholipids and allylic and diallylic protons. Certain classes of neutral lipids (cholesterol esters, fatty acyl chain (-COCH2-) and FAMEs) were also mildly increased in ADH− deer mice fed 1 or 2% ethanol. Only small increases were observed for allylic and diallylic protons, FAMEs and unsaturations in ADH+ deer mice fed 3.5% ethanol vs. pair-fed controls. PCA of NMR data showed increased clustering by gradual separation of ethanol-fed ADH− deer mice groups from their respective pair-fed control groups and corresponding ethanol-fed ADH+ deer mice groups. Our data indicate that dose of ethanol and hepatic ADH deficiency are two key factors involved in initiation and progression of alcoholic fatty liver disease. Further studies on characterization of individual lipid entities and associated metabolic pathways altered in our deer mouse model after different durations of ethanol feeding could be important to delineate mechanism(s) and identify potential biomarker candidate(s) of early stage ALD.

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Section: Introductionmentioning

confidence: 59%

Hepatic lipid profiling of deer mice fed ethanol using 1H and 31P NMR spectroscopy: A dose-dependent subchronic study

Fernando¹,

Bhopale²,

Boor³

et al. 2012

Toxicology and Applied Pharmacology

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“…and 40 animals were administered vehicle (water) 24 hours prior to sacrifice. The concentration of CE was determined by others not to directly cause liver damage (21) and was validated in a previously published study by our group (11). Based on the fraction of VC that is estimated to be metabolized to CE and its apparent volume of distribution in rodents, this concentration equates to ∼100 ppm inhalation exposure of VC over a short period of time.…”

Section: Methodsmentioning

confidence: 99%

Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice

Anders

Yeo

Kaelin

et al. 2016

Toxicology and Applied Pharmacology

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Background Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels. The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD). It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied. Methods Mice were administered chloroethanol (CE - a VC metabolite) or vehicle once, 10 weeks after being fed diets rich in saturated fatty acids (HSFA), rich in poly-unsaturated fatty acids (HPUFA), or the respective low-fat control diets (LSFA; LPUFA). Results In control mice, chloroethanol caused no detectable liver injury, as determined by plasma transaminases and histologic indices of damage. In HSFA-fed mice, chloroethanol increased HSFA-induced liver damage, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines, and markers of endoplasmic reticulum (ER) stress. Moreover, markers of inflammasome activation were increased, while markers of inflammasome inhibition were downregulated. In mice fed HPUFA all of these effects were significantly attenuated. Conclusions Chloroethanol promotes inflammatory liver injury caused by dietary fatty acids. This effect is far more exacerbated with saturated fat, versus poly-unsaturated fat; and strongly correlates with a robust activation of the NLRP3 inflammasome in the saturated fed animals only. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH.

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“…Examples of this are pentachlorophenol (Ansari et al 1995), tetrahydrocannabinol (Leighty et al 1976, Yisak et al 1987, the 1,1-di(4-chlorophenyl)-2,2,2-trichloroethane (DDT) metabolite 2,2 0 -di(4-chlorophenyl)-ethanol (DDOH) (Leighty et al 1980) and the asthma drug Budesonid (Tunek et al 1997), which have been observed to form esters with palmitic acid, stearic acid, oleic acid and/or linoleic acid. Fatty acid ester formation has also been shown for ethanol and haloethanols (Kaphalia and Ansari 1989, Bhat and Ansari 1990, Treloar et al 1996. The esters are formed by liver microsomal systems (Leighty et al 1980) and have been observed in in vivo experiments both retained in tissues and excreted in faeces (Leighty et al 1976).…”

Section: Introductionmentioning

confidence: 92%

Covalent binding of PCB metabolites to lipids: route of formation and characterization

2002

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1. After an oral dose of (14)C-labelled 3,3',4,4'-tetrachlorobiphenyl (CB-77), the conventional germ-free and bile-duct cannulated male Sprague-Dawley rat excreted approximately 80% of the dose in faeces and/or bile within 3 days. 2. For the germ-free and conventional rat, 15% of the dose was excreted via the faeces as metabolites covalently bound to lipids. Bile-duct-cannulated rats excreted similar amounts of lipid-bound metabolites in the bile. The lipid-bound metabolites appear to be formed in the liver and excreted via the bile, and the microflora did not seem essential for the formation of lipid-bound metabolites. 3. The novel CB-77 metabolites had chemical and physical properties similar to those of lipids with regard to solubility and polarity, as determined by partition characteristics on various chromatographic systems. 4. In addition to identification of hydroxylated CB-77 metabolites, several fatty acid esters of hydroxy-chlorobiphenyls were indicated and one hydroxy-tetrachlorobiphenylol palmitoate was identified, but fatty acid esters were minor metabolites. 5. Approximately 70% of the lipid-bound metabolites were present in the fraction that contained phospholipids. The formation of lipid-bound CB-77 metabolites seems a spontaneous reaction rather than an enzymatically catalysed reaction, as indicated by the large number of different lipid-bound metabolites.

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Hepatic fatty acid conjugation of 2‐chloroethanol and 2‐bromoethanol in rats

Cited by 29 publications

References 24 publications

Hepatic lipid profiling of deer mice fed ethanol using 1H and 31P NMR spectroscopy: A dose-dependent subchronic study

Hepatic lipid profiling of deer mice fed ethanol using 1H and 31P NMR spectroscopy: A dose-dependent subchronic study

Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice

Covalent binding of PCB metabolites to lipids: route of formation and characterization

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