Hepatotoxicity of Psychotropic Drugs

Selim, Khaled; Kaplowitz, Neil

doi:10.1002/hep.510290535

Cited by 103 publications

(57 citation statements)

References 64 publications

(79 reference statements)

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“…metabolites, such as N -hydroxynorcocaine ( 38 ) and norcocaine nitroxide ( 39 ), the majority of mechanistic studies have focused on the bioactivation of cocaine as well as subsequent covalent protein binding and disruption of redox homeostasis, including glutathione depletion and lipid peroxidation. Results from these studies have clearly indicated that metabolic activation and oxidative stress are indispensable components of cocaine toxicity (11)(12)(13). However, the adverse effects of cocaine exposure are not limited to the direct interaction with cytoprotective and cytotoxic pathways.…”

Section: Effects Of Fenofi Brate On Ppar ␣ -Targeted Genesmentioning

confidence: 99%

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

Shi

Yao

Gosnell

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org system ( 2, 3 ), cocaine causes liver injury in human and animal models ( 4-8 ). 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 ( 9, 10 ). Previous investigations of cocaine-elicited pathological and metabolic changes in animal models have yielded important insights on the initiation and development of cocaineinduced liver injury ( 11-13 ). First, biotransformation and bioactivation of cocaine and its metabolites are required to initiate cocaine-induced toxic events ( 14 ). Among those defi ned cocaine metabolism pathways, the hydrolysis reactions produce relatively nontoxic metabolites, whereas cytochrome P450 (P450) and fl avin-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 ( 15 ), glutathione depletion ( 16 ), and lipid peroxidation ( 17 ), occur in the cocaine-treated liver, although their roles in cocaine-induced hepatotoxicity are not fully defi ned. Lastly, the disruption of normal function of mitochondria and other intracellular organelles as well as the dysregulation of signaling pathways in cell death Abstract During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact infl uences 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 confi rmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cocaine, as one of the most widely abused psychological stimulants, is well known for causing addictive dependence and sudden death in its users ( 1 ). Besides its toxicity on the central nervous system (CNS) and the cardiovascular

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Section: Effects Of Fenofi Brate On Ppar ␣ -Targeted Genesmentioning

confidence: 99%

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

Shi

Yao

Gosnell

et al. 2012

Journal of Lipid Research

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“…Асимптоматско пролазно повећање трансаминаза (AST, ALT) и билирубина описано је код чак 50% пацијената лечених атипичним антипсихотицима, мада они ретко доводе до озбиљне хепатотоксичности (10). Ипак, неки од њих имају потенцијал да изазову озбиљну дисфункцију јетре, нарочито клозапин, оланзапин и рисперидон (11).…”

Section: уводunclassified

Clozapine and risperidone influence on metabolic parameters and liver function in patients with schizophrenia

Radonjić¹

2013

Medicinski casopis

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УВОДУ последњој деценији, антипсихотици друге генерације (атипични антипсихотици) показали су бројне предности у односу на антипсихотике прве генерације у погледу позитивних, негативних, когнитивних и афективних симптома и ређег јављања екстрапирамидалних нежељених ефеката (1, 2). Упркос овим неоспорним предностима, атипични антипсихотици (клозапин, оланзапин, рисперидон, кветиапин, арипипразол, зипрасидон)

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“…Chlorpromazine is well known to cause cholestatic liver injury clinically (43,44). It also induces cholestasis in IPRL, accompanying a flow disturbance (5).…”

Section: Suspected Toxicological Significancementioning

confidence: 99%

“…Tricyclic antidepressants also clinically lead to hepatocellular, and more commonly to cholestatic injury, although the incidence in humans is rare; the mechanism for this is still unclear (43,44). Acute serious toxicity is reported at plasma concentrations of 3.2 µM CLM (45).…”

Section: Suspected Toxicological Significancementioning

confidence: 99%

Intrahepatic Flow Disturbance: Possibility of a Hidden Cause of Drug Toxicity

Masuda

2006

J Pharmacol Sci

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Abstract. The liver has an intricate microvascular system that allows homogenous perfusion throughout the organ. However, the regulatory mechanisms of intrahepatic circulation are still unclear, and the effects of drugs on this system have rarely been reported. Oxethazaine, a topical anesthetic, was incidentally found to induce a consistent increase in portal pressure in the isolated perfused rat liver, which led us to characterize this phenomenon. For this, a vital staining method was developed to detect microcirculatory alterations in the isolated liver. Using this method, not only vasoconstrictors like endothelin-1, but the drugs oxethazaine and clomipramine, a tricyclic antidepressant, were found to induce flow redistribution to the deeper and hilar portions of the liver with minimal perfusion at the periphery, which was due to a short-circuit flow at the center owing to the constriction of the intrahepatic portal vein branches. Hepatic nerve stimulation also produced a similar flow disturbance. Since the portal pressure increases by these compounds were inhibited by the Rho-kinase inhibitors Y27632 and HA1077, portal vein branches may employ a Rho-kinase-dependent pathway for sustained contraction. However, oxethazaine, clomipramine, and endothelin-1 may activate this pathway differently. The intrahepatic flow disturbance could play a hidden role in drug toxicity of certain drugs.

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Hepatotoxicity of Psychotropic Drugs

Cited by 103 publications

References 64 publications

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

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

Clozapine and risperidone influence on metabolic parameters and liver function in patients with schizophrenia

Intrahepatic Flow Disturbance: Possibility of a Hidden Cause of Drug Toxicity

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