Cysteine Metabolism and Oxidative Processes in the Rat Liver and Kidney after Acute and Repeated Cocaine Treatment.

Danuta Kowalczyk-Pachel,Karolina Wydra,Elżbieta Lorenc-Koci,Małgorzata Filip,Ewa Nowak,Małgorzata Iciek,Magdalena Górny,Lidia Włodek,Ferenc Gallyas

doi:10.1371/journal.pone.0147238

Danuta Kowalczyk-Pachel, Karolina Wydra + Show 7 more

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https://doi.org/10.1371/journal.pone.0147238

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Abstract

The role of cocaine in modulating the metabolism of sulfur-containing compounds in the peripheral tissues is poorly understood. In the present study we addressed the question about the effects of acute and repeated (5 days) cocaine (10 mg/kg i.p.) administration on the total cysteine (Cys) metabolism and on the oxidative processes in the rat liver and kidney. The whole pool of sulfane sulfur, its bound fraction and hydrogen sulfide (H2S) were considered as markers of anaerobic Cys metabolism while the sulfate as a measure of its aerobic metabolism. The total-, non-protein- and protein- SH group levels were assayed as indicators of the redox status of thiols. Additionally, the activities of enzymes involved in H2S formation (cystathionine γ-lyase, CSE; 3-mercaptopyruvate sulfurtransferase, 3-MST) and GSH metabolism (γ-glutamyl transpeptidase, γ-GT; glutathione S-transferase, GST) were determined. Finally, we assayed the concentrations of reactive oxygen species (ROS) and malondialdehyde (MDA) as markers of oxidative stress and lipid peroxidation, respectively. In the liver, acute cocaine treatment, did not change concentrations of the whole pool of sulfane sulfur, its bound fraction, H2S or sulfate but markedly decreased levels of non-protein SH groups (NPSH), ROS and GST activity while γ-GT was unaffected. In the kidney, acute cocaine significantly increased concentration of the whole pool of sulfane sulfur, reduced the content of its bound fraction but H2S, sulfate and NPSH levels were unchanged while ROS and activities of GST and γ-GT were reduced. Acute cocaine enhanced activity of the CSE and 3-MST in the liver and kidney, respectively. Repeatedly administered cocaine enhanced the whole pool of sulfane sulfur and reduced H2S level simultaneously increasing sulfate content both in the liver and kidney. After repeated cocaine, a significant decrease in ROS was still observed in the liver while in the kidney, despite unchanged ROS content, a marked increase in MDA level was visible. The repeated cocaine decreased 3-MST and increased γ-GT activities in both organs but reduced GST in the kidney. Our results show that cocaine administered at a relatively low dose shifts Cys metabolism towards the formation of sulfane sulfur compounds which possess antioxidant and redox regulatory properties and are a source of H2S which can support mitochondrial bioenergetics.

Highlights

Cocaine, one of the most widespread and addictive drugs of abuse, is a fat-soluble alkaloid derived from the leaves of the South American plant Erytroxylon coca
For the first time we simultaneously assessed changes in the anaerobic and aerobic Cys metabolism and in the oxidative processes in the liver and kidney of rats treated with this drug of abuse
Our results indicate that in the tested tissues acute and repeated administration of cocaine affects thiol homeostasis and oxidative processes in a different way

Summary

Introduction

Cocaine (benzoylmethylecgonine), one of the most widespread and addictive drugs of abuse, is a fat-soluble alkaloid derived from the leaves of the South American plant Erytroxylon coca. Cocaine is mainly metabolized by plasma, liver and intestinal carboxylesterases that hydrolyze its ester groups leading to the formation of non-toxic metabolites [1,2,3,4]. The minor route of cocaine metabolism catalyzed in the liver by cytochrome P450 and flavin-containing monooxygenases involves the amine moiety transformations leading to the formation of oxidative metabolites [3,5,6,7,8,9]. It is believed that toxicity of high cocaine doses is the effect of redox cycling of some reactive metabolites that induces the excessive generation of reactive oxygen species (ROS) causing the oxidative stress and subsequent lipid peroxidation [6,7,8,9]. It is worth emphasizing that interactions of cocaine with membrane bound proteins [13] and disturbance in the mitochondrial respiratory chain are considered to be significant factors in the acute cocaine toxicity [14,15,16,17]

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