Addiction

Toxicol Appl Pharmacol. 2011 Sep 1;255(2):127-37.
Lipidomic changes in rat liver after long-term exposure to ethanol.
Fernando H, Bhopale KK, Kondraganti S, Kaphalia BS, Shakeel Ansari GA.
Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555, USA.

ABSTRACT: Alcoholic liver disease (ALD) is a serious health problem with significant morbidity and mortality. In this study we examined the progression of ALD along with lipidomic changes in rats fed ethanol for 2 and 3 months to understand the mechanism, and identify possible biomarkers. Male Fischer 344 rats were fed 5% ethanol or caloric equivalent of maltose-dextrin in a Lieber-DeCarli diet. Animals were killed at the end of 2 and 3 months and plasma and livers were collected. Portions of the liver were fixed for histological and immunohistological studies. Plasma and the liver lipids were extracted and analyzed by nuclear magnetic resonance (NMR) spectroscopy. A time dependent fatty infiltration was observed in the livers of ethanol-fed rats. Mild inflammation and oxidative stress were observed in some ethanol-fed rats at 3 months. The multivariate and principal component analysis of proton and phosphorus NMR spectroscopy data of extracted lipids from the plasma and livers showed segregation of ethanol-fed groups from the pair-fed controls. Significant hepatic lipids that were increased by ethanol exposure included fatty acids and triglycerides, whereas phosphatidylcholine (PC) decreased. However, both free fatty acids and PC decreased in the plasma. In liver lipids unsaturation of fatty acyl chains increased, contrary to plasma, where it decreased. Our studies confirm that over-accumulation of lipids in ethanol-induced liver steatosis accompanied by mild inflammation on long duration of ethanol exposure. Identified metabolic profile using NMR lipidomics could be further explored to establish biomarker signatures representing the etiopathogenesis, progression and/or severity of ALD.


Eur J Neurol. 2007 Jul;14(7):801-8.
Omega-6 and omega-3 fatty acids predict accelerated decline of peripheral nerve function in older persons.
Lauretani F(1), Bandinelli S, Bartali B, Cherubini A, Iorio AD, Blè A, Giacomini V, Corsi AM, Guralnik JM, Ferrucci L.
Tuscany Regional Health Agency, Florence, Italy.

ABSTRACT: Pre-clinical studies suggest that both omega-6 and omega-3 fatty acids have beneficial effects on peripheral nerve function. Rats feed a diet rich in polyunsaturated fatty acids (PUFAs) showed modification of phospholipid fatty acid composition in nerve membranes and improvement of sciatic nerve conduction velocity (NCV). We tested the hypothesis that baseline plasma omega-6 and omega-3 fatty acids levels predict accelerated decline of peripheral nerve function. Changes between baseline and the 3-year follow-up in peripheral nerve function was assessed by standard surface ENG of the right peroneal nerve in 384 male and 443 female participants of the InCHIANTI study (age range: 24-97 years). Plasma concentrations of selected fatty acids assessed at baseline by gas chromatography. Independent of confounders, plasma omega-6 fatty acids and linoleic acid were significantly correlated with peroneal NCV at enrollment. Lower plasma PUFA, omega-6 fatty acids, linoleic acid, ratio omega-6/omega-3, arachidonic acid and docosahexanoic acid levels were significantly predicted a steeper decline in nerve function parameters over the 3-year follow-up. Low plasma omega-6 and omega-3 fatty acids levels were associated with accelerated decline of peripheral nerve function with aging.


Crit Care Med. 2007 Oct;35(10):2367-74.
Conjugated primary bile salts reduce permeability of endotoxin through intestinal epithelial cells and synergize with phosphatidylcholine in suppression of inflammatory cytokine production.
Parlesak A(1), Schaeckeler S, Moser L, Bode C.
Nutritional Immunology Group, Biocentrum, Technical University of Denmark, Lyngby, Denmark. alpa@biocentrum.dtu.dk

OBJECTIVE: Endotoxemia was shown to be integral in the pathophysiology of obstructive jaundice. In the current study, the role of conjugated primary bile salts (CPBS) and phosphatidylcholine on the permeability of endotoxin through a layer of intestinal epithelial cells and the consequent activation of basolaterally cocultured human mononuclear leukocytes were measured.
DESIGN: In a coculture model, a layer of differentiated, confluent Caco-2 cells was apically stimulated with growth-arrested, nonpathogenic Escherichia coli.
SETTING: Basic human cell culture laboratory.
INTERVENTIONS: The effect of CPBS (0.5 mM and 1.5 mM), phosphatidylcholine (0.38 mM), and human bile (0.5% vol/vol) on the barrier function was assessed by the measurement of transepithelial electrical resistance, by endotoxin permeability through the intestinal epithelial cell layer, and by basolateral cytokine enzyme-linked immunosorbent assay measurement (tumor necrosis factor-[alpha], interleukins-6, -8, and -10). Micelles formed by CPBS were detected by dynamic light scattering. The association of endotoxin with CPBS micelles was tested by fluorescence resonance energy transfer.
MEASUREMENTS AND MAIN RESULTS: Apical addition of CPBS suppressed the permeability of endotoxins through the intestinal epithelial cell layer significantly. In parallel, apical supplementation of CPBS dose-dependently reduced the basolateral production of all cytokines measured. Apical phosphatidylcholine supplementation enhanced this effect significantly. CPBS formed micelles (diameter, 134 +/- 7 nm), which were able to bind endotoxin to their surface.
CONCLUSIONS: CPBS can reduce the permeation of endotoxin through intestinal epithelial cell layers by binding it to micelles. Thereby, the inflammatory processes beyond the mucosal surface are suppressed, an effect that is enhanced by phosphatidylcholine.


Rocz Akad Med Bialymst. 2005;50:7-20.
Pathogenesis and treatment of alcoholic liver disease: progress over the last 50 years.
Lieber CS.
Alcohol Research and Treatment Center, Section of Liver Disease and Nutrition, Bronx VA Medical Center, New York 10468, USA.

Fifty years ago the dogma prevailed that alcohol was not toxic to the liver and that alcoholic liver disease was exclusively a consequence of nutritional deficiencies. We showed, however, that liver pathology developed even in the absence of malnutrition. This toxicity of alcohol was linked to its metabolism via alcohol dehydrogenase which converts nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide-reduced form (NADH) which contributes to hyperuricemia, hypoglycemia and hepatic steatosis by inhibiting lipid oxidation and promoting lipogenesis. We also discovered a new pathway of ethanol metabolism, the microsomal ethanol oxidizing system (MEOS). The activity of its main enzyme, cytochrome P4502E1 (CYP2E1), and its gene are increased by chronic consumption, resulting in metabolic tolerance to ethanol. CYP2E1 also detoxifies many drugs but occasionally toxic and even carcinogenic metabolites are produced. This activity is also associated with the generation of free radicals with resulting lipid peroxidation and membrane damage as well as depletion of mitochondrial reduced glutathione (GSH) and its ultimate precursor, namely methionine activated to S-adenosylmethionine (SAMe). Its repletion restores liver functions. Administration of polyenylphosphatidylcholine (PPC), a mixture of unsaturated phosphatidylcholines (PC) extracted from soybeans, restores the structure of the membranes and the function of the corresponding enzymes. Ethanol impairs the conversion of beta-carotene to vitamin A and depletes hepatic vitamin A and, when it is given together with vitamin A or beta-carotene, hepatotoxicity is potentiated. Our present therapeutic approach is to reduce excess alcohol consumption by the Brief Intervention technique found to be very successful. We correct hepatic SAMe depletion and supplementation with PPC has some favorable effects on parameters of liver damage which continue to be evaluated. Similarly dilinoleoylphosphatidylcholine (DLPC), PPC’s main component, also partially opposes the increase in CYP2E1 by ethanol. Hence, therapy with SAMe +DLPC is now being considered.


Psychiatry Res. 2003 Aug 30;120(1):29-35.
Polyunsaturated fatty acid status and relapse vulnerability in cocaine addicts.
Buydens-Branchey L, Branchey M, McMakin DL, Hibbeln JR.
Department of Psychiatry, State University of New York-Health Science Center at Brooklyn and Veterans Affairs New York Harbor Healthcare System, Brooklyn Campus (11S/BK), 800 Poly Place, Brooklyn, NY 11209, USA.

There is mounting evidence that low levels of some polyunsaturated fatty acids (PUFAs) play a role in the pathophysiology of depressive and aggressive disorders, including homicides. There is also evidence derived mostly from the animal literature that PUFAs could play a role in the abuse of substances through their action on central serotonergic and dopaminergic systems that are both known to play a role in reward mechanisms. In this study, we explored the possibility that the relapse rates of cocaine addicts discharged after a period of detoxification on an inpatient unit would be associated with their PUFA status. Thirty-eight patients were enrolled in the study. PUFA status was assessed only at baseline, shortly after admission. Resumption of substance use was assessed 3 months, 6 months and 1 year following discharge. Thirty-two patients remained available for follow-up for the duration of the study. Subjects who relapsed at 3 months had significantly lower baseline levels of total n-6 PUFAs, linoleic acid (LA, 18:2n-6), arachidonic acid (AA, 20:4n-6) and total n-3 PUFAs when compared to non-relapsers by ANCOVAs with age and weight as covariates. Lower baseline total n-6 PUFAs, LA and AA continued to predict relapse 6 months and 12 months following discharge. Age, marital status, educational level, cocaine use parameters or psychopathology did not differ between relapsers and non-relapsers. In conclusion, low PUFA status at baseline was a better predictor of relapse than cocaine use, sociodemographic or clinical parameters. These data suggest, but do not prove, the existence of a causal relationship between n-6 or n-3 status and relapse vulnerability in cocaine addicts, and provide a rationale for the exploration of possible relationships between relapse to addictive disorders and PUFA status in observational and interventional trials.


Brain Res. 1999 Jul 10;834(1-2):207-10.
Phosphatidylcholine and phosphatidylethanolamine metabolites may regulate brain phospholipid catabolism via inhibition of lysophospholipase activity.
Fallbrook A(1), Turenne SD, Mamalias N, Kish SJ, Ross BM.
Human Neurochemical Pathology Laboratory, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada.

ABSTRACT: Brain levels of glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE), abundant metabolites of phosphatidylcholine and phosphatidylethanolamine, are increased in several disorders of the human brain. To determine whether accumulation of these compounds may alter phospholipid metabolism, we assessed the ability of GPE and GPC to modulate the activities of phospholipase A(2), lysophospholipase, and other enzymes involved in phospholipid metabolism, in preparations of human brain parietal cortex. GPC and GPE acted as competitive inhibitors of lysophospholipase activity, but failed to alter the activity of the other enzymes tested. Our results suggest that GPC and GPE may normally act to inhibit lysophospholipid hydrolysis, thereby reducing the rate of membrane phospholipid degradation.


Biochim Biophys Acta. 1998 Jun 29;1376(1):91-145.
Phases and phase transitions of the phosphatidylcholines.
Koynova R(1), Caffrey M.
Institute of Biophysics, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.

ABSTRACT: LIPIDAT (http://www.lipidat.chemistry.ohio-state.edu) is an Internet accessible, computerized relational database providing access to the wealth of information scattered throughout the literature concerning synthetic and biologically derived polar lipid polymorphic and mesomorphic phase behavior and molecular structures. Here, a review of the data subset referring to phosphatidylcholines is presented together with an analysis of these data. This subset represents ca. 60% of all LIPIDAT records. It includes data collected over a 43-year period and consists of 12,208 records obtained from 1573 articles in 106 different journals. An analysis of the data in the subset identifies trends in phosphatidylcholine phase behavior reflecting changes in lipid chain length, unsaturation (number, isomeric type and position of double bonds), asymmetry and branching, type of chain-glycerol linkage (ester, ether, amide), position of chain attachment to the glycerol backbone (1,2- vs. 1,3-) and head group modification. Also included is a summary of the data concerning the effect of pressure, pH, stereochemical purity, and different additives such as salts, saccharides, amino acids and alcohols, on phosphatidylcholine phase behavior. Information on the phase behavior of biologically derived phosphatidylcholines is also presented. This review includes 651 references.


Biochem Pharmacol. 1973 Nov 1;22(21):2731-41.
Effect of d-amphetamine on the turnover, synthesis and metabolism of brain phosphatidylcholine.
Hitzemann RJ, Loh HH.

ABSTRACT: The effect of acute and chronic d-amphetamine treatment on the synthesis, metabolism and turnover of The effect of acute and chronic d-amphetamine treatment on the synthesis, metabolism and turnover of 14C-choline labeled phosphatidylcholine was measured in discrete regions of the rat brain. Chronic d-amphetamine treatment was found to inhibit the turnover of 14C-phosphatidylcholine in the cortex, cerebellum, hypothalamus, diencephalon, brain stem and caudate nucleus. Acute d-amphetamine treatment was found to inhibit the incorporation of 14C-choline into phosphatidylcholine only in the cortex and cerebellum. Studies in vitro suggest that d-amphetamine inhibits cortical phosphatidylcholine synthesis at the cytidine diphosphorylcholine diglyceride transferase step. d-Amphetamine was not found to alter the base-exchange reaction or phospholipase C activity.


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