Evaluation of CYP2D, CYP1A2 and distribution of tetrandrine, fangchinoline in the brain, liver, and kidney of wistar rats after short-term exposure to Cyclea peltata

Abstract

Background: Cyclea peltata (CP) roots are used in Indian traditional medicine to treat various diseases. However, short-term toxic effects of CP are completely unknown. Objectives: The aim of this study is to evaluate short-term toxic effects of CP, tissue distribution of bioactive alkaloids tetrandrine, fangchinoline in the brain, liver, kidney, and mRNA expression of CYP2D, CYP1A2 after CP administration. Materials and Methods: In vitro toxicity evaluation of CP was carried out using annexin 5/propidium iodide assay with or without CP treatment in L 929 cell line. And in vivo short term toxicity of CP was evaluated in Wistar rats for 28 days. Liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) based tissue distribution of bioactive molecules was assessed and mRNA expression of CYP1A2, CYP2D, CYP2C6, and CYP2E1 were estimated using qRT- polymerase chain reaction. Results: In vitro toxicity of 70% aqueous ethanol extract of CP 50 μg/mL showed 62.18% cell viability. Oral administration of CP (50, 500 mg/kg) did not cause any clinical, hematological, serum biochemical, and histopathological changes in rats, whereas CP (1000 mg/kg) showed infiltrative changes in the kidney and lungs. Imbalance in oxidative stress and antioxidant defense was reflected as elevated MDA levels in rat liver. LC-Q-TOF-MS studies could detect tissue distribution of bioactive alkaloids tetrandrine, fangchinoline and their decomposed masses in the liver and kidney, whereas tetrandrine and its decomposed molecule (580.3) ([M + H]-43) + could cross blood–brain barrier and were detected in the brain. Evaluation of mRNA expression revealed dose-dependent increase in expression of CYP2D and CYP1A2. Conclusion: Oral administration of CP 500 mg/kg for 28 days is safer in rats due to balanced antioxidant defense. Imbalance in antioxidant defense enzymes and toxic metabolites formed through the escalation of CYP2D, CYP1A2 and metabolism of bioactive alkaloids of CP may be the reason for infiltrative changes in kidney, lungs observed after 28 days CP 1000 mg/kg administration.