<abstract xml:lang="en" xmlns="http://www.w3.org/1999/xhtml">The aim of this study was to trace D-amphetamine toxicity in isolated rat hepatocytes and to elucidate a possible involvement of CYP3A in the mechanisms of its toxicity. To this end, male Wistar rats were treated with nifedipine (5 mg kg-1<italic>i.p.</italic>, 5 days), a substrate and inducer of CYP3A. Hepatocytes isolated from nifedipine-treated and control rats were incubated with D-amphetamine at a concentration of 100 μmol L-1, which was determined to be an average toxic concentration (TC50) for the compound. To evaluate the possible toxic effects of D-amphetamine on freshly isolated rat hepatocytes, we assessed the following parameters: cell viability, lactate dehydrogenase (LDH) activity, and glutathione (GSH).The results showed that nifedipine potentiated amphetamine cytotoxicity <italic>in vitro</italic>, as follows: cell viability dropped by 65% (p>0.001), GSH by 80% (p>0.001), and LDH activity increased by 190% (p>0.001). To clarify the role of nifedipine in amphetamine cytotoxicity, we used amiodarone, a substrate and an inhibitor of CYP3A. Pre-incubation of nifedipine-treated hepatocytes with amiodarone (14 μmol L-1) significantly lowered amphetamine cytotoxicity.Our results confirmed the toxicity of D-amphetamine in isolated rat hepatocytes and the involvement of CYP3A in its metabolism and hepatotoxicity.</abstract>

The aim of this study was to trace D-amphetamine toxicity in isolated rat hepatocytes and to elucidate a possible involvement of CYP3A in the mechanisms of its toxicity. To this end, male Wistar rats were treated with nifedipine (5 mg kg-1i.p., 5 days), a substrate and inducer of CYP3A. Hepatocytes isolated from nifedipine-treated and control rats were incubated with D-amphetamine at a concentration of 100 μmol L-1, which was determined to be an average toxic concentration (TC50) for the compound. To evaluate the possible toxic effects of D-amphetamine on freshly isolated rat hepatocytes, we assessed the following parameters: cell viability, lactate dehydrogenase (LDH) activity, and glutathione (GSH).The results showed that nifedipine potentiated amphetamine cytotoxicity in vitro, as follows: cell viability dropped by 65% (p>0.001), GSH by 80% (p>0.001), and LDH activity increased by 190% (p>0.001). To clarify the role of nifedipine in amphetamine cytotoxicity, we used amiodarone, a substrate and an inhibitor of CYP3A. Pre-incubation of nifedipine-treated hepatocytes with amiodarone (14 μmol L-1) significantly lowered amphetamine cytotoxicity.Our results confirmed the toxicity of D-amphetamine in isolated rat hepatocytes and the involvement of CYP3A in its metabolism and hepatotoxicity.

D-Amphetamine Toxicity in Freshly Isolated Rat Hepatocytes: A Possible Role of CYP3A

Laboratory of Drug Metabolism and Drug Toxicity, Department of Pharmacology, Pharmacotherapy, and Toxicology, Faculty of Pharmacy, Medical University Sofia, Sofia, Bulgaria

Archives of Industrial Hygiene and Toxicology

The aim of this study was to trace D-amphetamine toxicity in isolated rat hepatocytes and to elucidate a possible involvement of CYP3A in the mechanisms of its...

D-Amphetamine Toxicity in Freshly Isolated Rat Hepatocytes: A Possible Role of CYP3A

Published Online: Jul 06, 2009

Page range: 139 - 145

DOI: https://doi.org/10.2478/10004-1254-60-2009-1912

Keywords
amiodarone, amphetamine cytotoxicity, nifedipine

This content is open access.

D-Amphetamine Toxicity in Freshly Isolated Rat Hepatocytes: A Possible Role of CYP3A

Published Online: Jul 06, 2009

Page range: 139 - 145

DOI: https://doi.org/10.2478/10004-1254-60-2009-1912

Keywordsamiodarone, amphetamine cytotoxicity, nifedipine

This content is open access.

Keywords
amiodarone, amphetamine cytotoxicity, nifedipine