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

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 -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 µmol L -1 , which was determined to be an average toxic concentration (TC 50 ) 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 ) signifi cantly lowered amphetamine cytotoxicity. Our results confi rmed the toxicity of D-amphetamine in isolated rat hepatocytes and the involvement of CYP3A in its metabolism and hepatotoxicity.

Effects of Catha Edulis Abuse on Glucose, Lipid Profiles and Liver Histopathology in Rabbit

“…Cathinone is similar in structure and pharmacological activity to amphetamine [6], [7]. Damphetamine is known to exert different forms of hepatotoxicity in-vivo and in-vitro when tested on hepatocytes [8]. khat is expected to cause similar toxic effects on the liver but the available data are few and sporadic.…”