D-amphetamine toxicity in freshly isolated rat hepatocytes: a possible role of CYP3A.
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) i.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 micromol 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 micromol 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.
Vitcheva
Vessela
V
Laboratory of Drug Metabolism and Drug Toxicity, Department of Pharmacology, Pharmacotherapy, and Toxicology, Faculty of Pharmacy, Medical University Sofia, Sofia, Bulgaria. vesselavitcheva@yahoo.com
Kondeva-Burdina
Magdalena
M
Mitcheva
Mitka
M
D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D002491:Central Nervous System Agents / Q000633:toxicity*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D003913:Dextroamphetamine / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D002491:Central Nervous System Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D051544:Cytochrome P-450 CYP3A; D009543:Nifedipine; D000638:Amiodarone; D003913:Dextroamphetamine