Lipidomic profiling reveals protective function of fatty acid oxidation in cocaine-induced hepatotoxicity

Abstract

During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor α (PPARα)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury. During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor α (PPARα)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury. Cocaine, as one of the most widely abused psychological stimulants, is well known for causing addictive dependence and sudden death in its users (1Nutt D. King L.A. Saulsbury W. Blakemore C. Development of a rational scale to assess the harm of drugs of potential misuse.Lancet. 2007; 369: 1047-1053Abstract Full Text Full Text PDF PubMed Scopus (829) Google Scholar). Besides its toxicity on the central nervous system (CNS) and the cardiovascular system (2Laso W. Neurochemical and pharmacological aspects of cocaine-induced seizures.Pol. J. Pharmacol. 2001; 53: 57-60PubMed Google Scholar, 3Knuepfer M.M. Cardiovascular disorders associated with cocaine use: myths and truths.Pharmacol. Ther. 2003; 97: 181-222Crossref PubMed Scopus (65) Google Scholar), cocaine causes liver injury in human and animal models (4Cascales M. Alvarez A. Gasco P. Fernandez-Simon L. Sanz N. Bosca L. Cocaine-induced liver injury in mice elicits specific changes in DNA ploidy and induces programmed death of hepatocytes.Hepatology. 1994; 20: 992-1001Crossref PubMed Scopus (46) Google Scholar–5Shuster L. Quimby F. Bates A. Thompson M.L. Liver damage from cocaine in mice.Life Sci. 1977; 20: 1035-1041Crossref PubMed Scopus (84) Google Scholar, 6Jover R. Ponsoda X. Gomez-Lechon M.J. Herrero C. del Pino J. Castell J.V. Potentiation of cocaine hepatotoxicity by ethanol in human hepatocytes.Toxicol. Appl. Pharmacol. 1991; 107: 526-534Crossref PubMed Scopus (34) Google Scholar, 7Kothur R. Marsh F. Posner G. Liver function tests in nonparenteral cocaine users.Arch. Intern. Med. 1991; 151: 1126-1128Crossref PubMed Scopus (19) Google Scholar, 8Cantilena L.R. Cherstniakova S.A. Saviolakis G. Kahn R. Elkashef A. Rose L. Vocci F. Prevalence of abnormal liver-associated enzymes in cocaine experienced adults versus healthy volunteers during phase 1 clinical trials.Contemp. Clin. Trials. 2007; 28: 695-704Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). As diminished liver function contributes to various adverse health effects, including the dysfunction of CNS and cardiovascular system and the disruption of intermediary metabolism, cocaine-induced hepatotoxicity has been linked to the mortality in cocaine abusers (9Porter J.M. Sussman M.S. Rosen G.M. Cocaine-induced hepatotoxicity.Hepatology. 1988; 8: 1713Crossref PubMed Scopus (3) Google Scholar, 10Wanless I.R. Dore S. Gopinath N. Tan J. Cameron R. Heathcote E.J. Blendis L.M. Levy G. Histopathology of cocaine hepatotoxicity. Report of four patients.Gastroenterology. 1990; 98: 497-501Abstract Full Text PDF PubMed Scopus (120) Google Scholar). Previous investigations of cocaine-elicited pathological and metabolic changes in animal models have yielded important insights on the initiation and development of cocaine-induced liver injury (11Boelsterli U.A. Goldlin C. Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites.Arch. Toxicol. 1991; 65: 351-360Crossref PubMed Scopus (103) Google Scholar–12Selim K. Kaplowitz N. Hepatotoxicity of psychotropic drugs.Hepatology. 1999; 29: 1347-1351Crossref PubMed Scopus (99) Google Scholar, 13Kloss M.W. Rosen G.M. Rauckman E.J. Cocaine-mediated hepatotoxicity. A critical review.Biochem. Pharmacol. 1984; 33: 169-173Crossref PubMed Scopus (142) Google Scholar). First, biotransformation and bioactivation of cocaine and its metabolites are required to initiate cocaine-induced toxic events (14Kovacic P. Role of oxidative metabolites of cocaine in toxicity and addiction: oxidative stress and electron transfer.Med. Hypotheses. 2005; 64: 350-356Crossref PubMed Scopus (102) Google Scholar). Among those defined cocaine metabolism pathways, the hydrolysis reactions produce relatively nontoxic metabolites, whereas cytochrome P450 (P450) and flavin-containing monooxygenases (FMO)-mediated N-demethylation and N-oxidation reactions are responsible for generating reactive metabolites, such as N-hydroxynorcocoaine and norcocaine nitroxide. Second, oxidative stress-related events, including covalent binding to proteins (15Evans M.A. Role of protein binding in cocaine-induced hepatic necrosis.J. Pharmacol. Exp. Ther. 1983; 224: 73-79PubMed Google Scholar), glutathione depletion (16Masini A. Gallesi D. Giovannini F. Trenti T. Ceccarelli D. Membrane potential of hepatic mitochondria after acute cocaine administration in rats–the role of mitochondrial reduced glutathione.Hepatology. 1997; 25: 385-390PubMed Google Scholar), and lipid peroxidation (17Kloss M.W. Rosen G.M. Rauckman E.J. N-demethylation of cocaine to norcocaine. Evidence for participation by cytochrome P-450 and FAD-containing monooxygenase.Mol. Pharmacol. 1983; 23: 482-485PubMed Google Scholar), occur in the cocaine-treated liver, although their roles in cocaine-induced hepatotoxicity are not fully defined. Lastly, the disruption of normal function of mitochondria and other intracellular organelles as well as the dysregulation of signaling pathways in cell death and survival leads to progressive necrosis and apoptosis of hepatocytes (18Zimmerman E.F. Potturi R.B. Resnick E. Fisher J.E. Role of oxygen free radicals in cocaine-induced vascular disruption in mice.Teratology. 1994; 49: 192-201Crossref PubMed Scopus (50) Google Scholar–19Vergeade A. Mulder P. Vendeville-Dehaudt C. Estour F. Fortin D. Ventura-Clapier R. Thuillez C. Monteil C. Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: prevention by the targeted antioxidant Med. 49: PubMed Scopus Google Scholar, A. C. D. J. cocaine administration reactive oxygen species and induces antioxidant activity in 2005; PubMed Scopus Google Scholar). have yielded on cocaine-induced hepatotoxicity, on this toxic the the metabolic events and the progression of cocaine-induced liver injury has not been the liver is the most important metabolic in the is by the and of the targeted However, the in and have an for the metabolic in a the of and and the of 2003; PubMed Scopus Google C. in 2007; PubMed Scopus Google Scholar, and of PubMed Scopus Google Scholar). and of and analyses have to the of that investigations of and A. L.M. J. R. potential role for in PubMed Scopus Google C. K. M. J.M. that hepatic 1 and acute Full Text Full Text PDF PubMed Scopus Google Scholar, X. D. C. of as a of ethanol Full Text Full Text PDF PubMed Scopus (46) Google Scholar). In a study has revealed the potential role of and metabolism in cocaine S. P. W. R. in and metabolism in cocaine addiction: a PubMed Scopus Google Scholar). In this study, the influences of cocaine treatment on the of serum and liver by the from the cocaine-induced disruption of fatty acid metabolism Cotreatment of an of peroxisome proliferator-activated receptor α was to the role of fatty acid oxidation in cocaine-induced liver injury. and acid from Cocaine, and by the on was from was from was from and from mice, in this study of administration of cocaine on hepatic and glutathione in Pharmacol. 1990; PubMed Scopus Google Scholar). in a of animal a with and and treatment in with animal study by the and cocaine treatment, cocaine was in a and a of by for three fenofibrate treatment, fenofibrate was in a and a of by cocaine and fenofibrate fenofibrate was cocaine on days and of cocaine treatment. control mice with Serum samples by prior to treatment and the of day of cocaine treatment, and samples by mice in metabolic for Liver and other samples after samples for of liver for and with and for and with for lipid Cocaine-induced liver injury was by serum and disruption of fatty acid metabolism was by the of serum and hepatic triacylglycerol (TAG) a assay of lipid peroxidation was by acid reactive assay liver and as of lipid peroxidation and Med. 1990; PubMed Scopus Google Scholar). liver was in of of liver with of of was by for and with an of acid for in a of was a of serum was by one of serum with of and for from the liver on the of and A of lipid and J. PubMed Scopus Google Scholar). Liver samples in and with and separation was by in the phase was and in A of serum liver lipid was an system and by a of phase from to acid a was a for and and for was and for and for and and was as and and as the was with and by the of the and in and and by in was with from to and of serum samples by A multivariate on and and was and of was by the versus the in the was and by and on the and of the multivariate including and to to the serum and liver lipid from control and cocaine-treated mice. in the in a of defined multivariate by to the and to the separation of in a of C. in 2007; PubMed Scopus Google Scholar, M. M. E. J. the of and 20: Scopus Google Scholar). of by and with in serum and liver lipid was by was as the by the the of and the of and with a with a from to 1 mitochondrial activity was by the of of and on hepatic mitochondrial function in the 1983; PubMed Scopus Google Scholar). from the liver by liver metabolism in Sci. 2003; PubMed Scopus Google Scholar). of with liver mitochondria in a and 1 in a of for reactions by of was on the of after the of cocaine metabolism was by of cocaine metabolites in the of the and of cocaine in a the of cocaine metabolites and their C. X. M.A. S. A of metabolism in the a multivariate Toxicol. 2007; 20: PubMed Scopus Google Scholar). of cocaine metabolites during three-day cocaine treatment by the of the of in the of cocaine was from the of mice was from 1 with and are in reactions with a system expression the and to are as was with for with the development of cocaine-induced hepatotoxicity, mice with of cocaine by for three of liver by and revealed the progression of cocaine-induced liver injury and day hepatocytes with increased but cell death was day hepatocytes in the centrilobular to and to and lipid day necrotic hepatocytes the central with and the development of was in the and with the serum and activity remained unchanged on day 1 but increased on day and of cocaine treatment and which that cocaine-induced damage on hepatocytes this is a subacute toxic of an acute on the of lipid and in cocaine-treated liver, the of lipid accumulation was by TAG in the liver and liver and serum TAG increased significantly after one of cocaine However, the serum TAG level remained largely unchanged after day whereas the hepatic TAG level increased on day of treatment to the in hepatic TAG the of liver was elevated on days 1 and of cocaine treatment peroxidation was by in the liver. level on day 1 of cocaine treatment, but was not increased Overall, the of hepatic TAG on day of cocaine treatment the with the development of necrosis in the liver and the of transaminase from the liver. changes in hepatic TAG level that metabolic events and to the and on days 1 and of cocaine treatment. the metabolic events associated with subacute hepatotoxic of the changes in the serum samples and liver lipid the and from by multivariate a by a was to the separation of serum samples the of cocaine treatment that cocaine the of serum in a time-dependent the of serum metabolites to the development of cocaine-induced liver injury. Serum to the of cocaine and control in a of to the of which are and acylcarnitines and with in and was and with the whereas the and fatty acid of and the of the of in the was not of their in the of serum revealed of changes in serum which the First, of long-chain acylcarnitines on days and of cocaine treatment, including and Second, the of and but the of and that the and of fatty in reduced after cocaine treatment. is by the of the of and which and fatty and the of and which and the of species on day of cocaine treatment, including and the time-dependent separation the control and cocaine-treated liver lipid was observed and the lipid species to the separation to those serum lipid after three-day cocaine after of serum metabolites to cocaine treatment is in most revealed by the of in by and of was its from a in a acid of by their but their and in and was not in a changes in serum lipid species after three-day cocaine treatment. of and in the as and control and cocaine-treated of serum metabolites to cocaine treatment is in most revealed by the of in by and of was its from a in a acid of by their but their and in and was not Among changes in the and the in the of long-chain acylcarnitines is to cocaine-induced hepatic due to their as specific of mitochondrial this the of in serum and liver during the three-day cocaine treatment results that in serum and liver remained unchanged on day 1 of cocaine treatment, was significantly elevated on day and was increased on day that acylcarnitine in the liver and was serum after cocaine treatment. inhibition of fatty acid as by the accumulation of was confirmed by the in vitro mitochondrial of by mitochondria was significantly reduced on day with other acid oxidation is by L. W. of PubMed Scopus Google Scholar). the role of fatty acid oxidation in cocaine-induced hepatotoxicity, a was to the mice on three days of cocaine treatment. results of and that fenofibrate was cocaine-induced changes in the centrilobular of the liver, as by the of necrotic and in the liver with cocaine and fenofibrate and with the of mice, including and serum and hepatic remained in normal in to the changes in the mice and of fenofibrate was confirmed by the of cocaine-induced level in the liver fenofibrate treatment was in the liver from cocaine-induced and other the of with fenofibrate one day and days after cocaine treatment not as as the the of fenofibrate to and the elevation of serum by three-day cocaine treatment. As a not enzymes and important in lipid metabolism but many enzymes M. proliferator-activated receptor a pharmacological with a PubMed Scopus Google Scholar, F. S. A. J.M. M. P. P. T. aspects of of lipid and metabolism revealed a 2007; PubMed Scopus Google Scholar). cocaine-induced hepatotoxicity is by cocaine metabolism, the of reactive cocaine metabolites, the of fenofibrate on cocaine metabolism of cocaine metabolites on days 1 and of the that the of reactive N-demethylation metabolites, and norcocaine on day their on day whereas an was observed for and nontoxic metabolites by the hydrolysis of cocaine that the bioactivation of cocaine was by with observed time-dependent fenofibrate not cocaine metabolism, the cocaine in the was to that in the on day 1 and day the of fenofibrate on cocaine-induced liver injury not due to the of cocaine changes associated with the of fenofibrate of serum samples from and control results separation of four in the of a three Besides control and cocaine the separation of the from the was fenofibrate significantly the lipid of cocaine-treated mice. serum to the of the cocaine from the and control in an and to 1 of their in serum revealed the of fenofibrate the cocaine-induced in the fenofibrate the cocaine-induced acylcarnitine accumulation and the in and species the liver revealed separation species to the separation with in serum of serum and hepatic from the and of fenofibrate was to the from the that the of fenofibrate with cocaine the cocaine-induced of in serum and liver and the treatment of fenofibrate and accumulation of fenofibrate was due to the of mitochondrial function in cocaine-treated mice, as the mitochondrial of was in the mice of fenofibrate and cocaine on genes was by the expression of and 1 three genes in mitochondrial and turnover. As fenofibrate treatment increased the expression of genes of activity was observed from the treatment of fenofibrate and cocaine to the of expression of and the of genes and the of mitochondrial activity that the of fenofibrate cocaine-induced lipid accumulation and hepatotoxicity was due to the of fatty acid the results from the administration of fenofibrate that of genes by fenofibrate was correlated with the cocaine-induced liver injury. of cocaine-induced liver injury have been for three due to the of cocaine as one of the most in (1Nutt D. King L.A. Saulsbury W. Blakemore C. Development of a rational scale to assess the harm of drugs of potential misuse.Lancet. 2007; 369: 1047-1053Abstract Full Text Full Text PDF PubMed Scopus (829) Google Scholar). the of reactive cocaine metabolites, such as M.L. L. K. Cocaine-induced hepatic necrosis in role of cocaine Pharmacol. 28: PubMed Scopus (120) Google and norcocaine Liver toxicity from norcocaine an of Pharmacol. Exp. Ther. Google Scholar), the of have on the bioactivation of cocaine as well as covalent protein binding and disruption of including glutathione depletion and lipid from have that metabolic and oxidative stress are of cocaine toxicity (11Boelsterli U.A. Goldlin C. Biomechanisms of cocaine-induced hepatocyte injury mediated by the formation of reactive metabolites.Arch. Toxicol. 1991; 65: 351-360Crossref PubMed Scopus (103) Google Scholar–12Selim K. Kaplowitz N. Hepatotoxicity of psychotropic drugs.Hepatology. 1999; 29: 1347-1351Crossref PubMed Scopus (99) Google Scholar, 13Kloss M.W. Rosen G.M. Rauckman E.J. Cocaine-mediated hepatotoxicity. A critical review.Biochem. Pharmacol. 1984; 33: 169-173Crossref PubMed Scopus (142) Google Scholar). However, the adverse of cocaine are not to the with and As a of cocaine and in and Neurochemical of cocaine with Pharmacol. Sci. 1988; Full Text PDF PubMed Scopus Google Scholar). the of are in the of and lipid metabolism L. and intermediary 1977; Full Text PDF PubMed Scopus Google E. G. K. M. J. P. E. metabolism and Med. 2007; PubMed Scopus Google Scholar, M. on Google Scholar, M. of on lipid PubMed Google Scholar), cocaine is to significantly intermediary events, including the of and metabolism L. E. of cocaine and on acid and oxygen in Pharmacol. Toxicol. PubMed Scopus Google Scholar, and in metabolism in Appl. PubMed Scopus (3) Google Scholar), as well as the elevation of cardiac and of cocaine on the liver of the Full Text PDF Google Scholar), this However, the exact of cocaine on intermediary metabolism remain largely unknown. In the role of intermediary metabolism in cocaine-induced hepatotoxicity has not been Cocaine-induced fatty liver in animal and human has been M. D. W. of the of cocaine in PubMed Scopus Google Scholar, of cocaine on the liver of the Full Text PDF Google hepatotoxicity during protein of J. Pharmacol. PubMed Scopus Google Scholar, R. E. S. of cocaine users from the of a Clin. PubMed Scopus Google Scholar). In this study, a of fatty liver development in subacute treatment of cocaine was hepatic TAG level increased on days 1 and of cocaine treatment, whereas serum TAG level increased on day 1 but remained largely unchanged with serum TAG the of hepatic TAG was better correlated to the results of and which that development of and of transaminase activity after day 1 and the causes the of hepatic TAG level insights on cocaine-induced hepatotoxicity. TAG level is by in TAG in the liver, which and of fatty TAG TAG fatty acid and TAG In this study, revealed that long-chain acylcarnitine in serum and liver well correlated to the progression of hepatotoxicity and and the acylcarnitine accumulation in was confirmed by reduced by the mitochondria from cocaine-treated liver that cocaine treatment of mitochondrial of the of fatty acid oxidation in TAG and metabolism, results revealed a for the development of and liver toxicity in subacute cocaine treatment. Mitochondrial dysfunction as a in cocaine toxicity has been the of of hepatic mitochondria in mice after cocaine treatment and a and time-dependent of mitochondrial potential (16Masini A. Gallesi D. Giovannini F. Trenti T. Ceccarelli D. Membrane potential of hepatic mitochondria after acute cocaine administration in rats–the role of mitochondrial reduced glutathione.Hepatology. 1997; 25: 385-390PubMed Google Scholar, M.W. D. Rauckman E.J. Rosen G.M. of cocaine hepatotoxicity.Hepatology. PubMed Scopus (46) Google Scholar). A study mitochondria that cocaine R. S. L. G. M. acute cocaine toxicity in potential by metabolic PubMed Scopus Google Scholar). of cocaine-elicited inhibition of hepatic in in this study the of mitochondria in cocaine-induced hepatotoxicity. Besides the inhibition of mitochondrial fatty acid oxidation has been as a of the hepatotoxicity by many and including C. Serum inhibition of fatty acid the of as a of Toxicol. PubMed Scopus Google Scholar), and D. of mitochondrial as a of Ther. PubMed Scopus Google Scholar). of fatty acid oxidation function are the disruption of metabolism and the accumulation of TAG and fatty changes other metabolic events, as well as the of hepatocytes to oxidative stress and In the of which the disruption of metabolism, and the of lipid peroxidation which oxidative have been observed in cocaine-treated liver Cocaine-induced stress in antioxidant enzymes and Pharmacol. Exp. Ther. Google Scholar). to the metabolic events associated with fatty acid one in this study was the of in serum TAG level on day of cocaine treatment in to the in hepatic TAG level fatty not for oxidative metabolism in the liver TAG and the and lipid PubMed Scopus Google Scholar). has been that TAG protein which is responsible for is by other known of mitochondrial P. A. A. D. of for in 2003; PubMed Scopus Google Scholar). this contributes to cocaine-induced TAG accumulation and toxicity in the liver the exact mitochondrial of cocaine in liver was not revealed by this study, a potential the of inhibition on day but not day of cocaine treatment, was revealed by the of cocaine metabolites, which that metabolites, norcocaine and significantly increased on day whereas the level of a of significantly is known that oxidative metabolites of cocaine are responsible for cocaine-induced of mitochondrial function and of reactive oxygen species (14Kovacic P. Role of oxidative metabolites of cocaine in toxicity and addiction: oxidative stress and electron transfer.Med. Hypotheses. 2005; 64: 350-356Crossref PubMed Scopus (102) Google Scholar, F. U.A. of cocaine and its oxidative metabolites on mitochondrial and of reactive oxygen Pharmacol. PubMed Scopus Google Scholar). the of their with acylcarnitine in serum and liver that the increased oxidative metabolism of cocaine to the cocaine-induced impairment of mitochondrial the of cocaine metabolites on acylcarnitine level in their to cocaine-induced of of fenofibrate in this study confirmed the of fatty acid oxidation in cocaine-induced hepatotoxicity As an of receptor fenofibrate the expression of genes administration of fenofibrate with cocaine treatment the adverse of cocaine on TAG lipid acylcarnitine and activity and cocaine metabolism which that the of pathways, fatty acid metabolism, is the the of and other have been widely to in clinical have TAG in the and of human P. J. N. T. D. J. of and of damage in cocaine Full Text Full Text PDF PubMed Scopus Google Scholar, C. A. R. J. D. S. as an of cardiac by Google Scholar). on the of fenofibrate cocaine-induced hepatotoxicity in this study and the of on and cardiovascular is to that and on cocaine users metabolic of mitochondrial In this potential of in the cocaine toxicity in was by the observed from administration of fenofibrate in this study Besides long-chain acylcarnitines as the of cocaine-induced hepatotoxicity, and analyses of serum and liver in this study revealed changes in the of phospholipid including and as well as the of fatty and the of in the of the of time-dependent changes that lipid species after cocaine whereas better correlated to the of liver injury the of together with liver by fenofibrate which their to cocaine-induced to changes is the to the changes by ethanol R. R. M.J. hepatic lipid metabolism in mice a targeted and expression Full Text Full Text PDF PubMed Scopus Google Scholar, M.A. activity is by ethanol and increased by Clin. Exp. 1994; PubMed Scopus Google Scholar), such as the of lipid species and the and species and of observed changes in the is their potential to the of such as the and of fatty D. J. E. J.M. J.V. of hepatic fatty acid and expression in and Full Text Full Text PDF PubMed Scopus Google Scholar). changes in the are events in hepatotoxicity and contributes to changes Overall, the of animal and in this study the of cocaine-induced changes in lipid inhibition of mitochondrial fatty acid oxidation was as a of cocaine-induced hepatotoxicity, and the of fenofibrate a potential in the hepatic of cocaine in clinical the on for the cocaine and cocaine metabolites in this with 1 cocaine central nervous system cocaine control flavin-containing and multivariate norcocaine cytochrome P450 to peroxisome proliferator-activated receptor α triacylglycerol acid reactive