Artecxin induced mitochondrial membrane permeability transition (MMPT) pore opening in rat liver

Abstract

Artecxin is a brand of Artemisinin combined antimalarial drug containing the biotransformed metabolite of Artemisinin ‐ dihydroartemisinin (32 mg), Piperaquine phosphate (160 mg) and Trimethoprim (90 mg). However, there is paucity of information on the modulatory effects of Artecxin on the mitochondria. The present study was designed to evaluate the effect of low (6.8 mg/kg), therapeutic (13.6 mg/kg) and over (27.2 mg/kg) doses of Artecxin on mitochondrial membrane permeability transition (MMPT) pore opening and biomarkers of liver and kidney functions. Twenty male Wistar strain albino rats (150–200g) were divided into four groups of five animals each. Groups I, II, III, IV received distilled water, 6.8 mg/kg, 13.6 mg/kg, and 27.2 mg/kg of Artecxin, respectively. Treatments were administered for 2 days at 0, 8, 24 and 32 hs. Degree of swelling (MMPT) was monitored spectrophotometrically as decreases in absorbance at 540 nm. Artecxin at 6.8, 13.6 and 27.2 mg/kg induced 16.7, 16.7 and 40 % opening of the MMPT pore. In the presence of Ca2+MMPT was opened by 54.9 and 26 % in the 13.6 and 27.2 mg/kg treated rats. Spermine (inhibitor) inhibited Ca2+‐induced pore opening by 66.7, 59 and 56.6 % in the 6.8 mg/kg, 13.6 mg/kg, and 27.2 mg/kg treated rats, respectively. Serum levels of creatinine and urea were not significantly (p<0.05) different from control except at 27.2 mg/kg Artecxin. The presence of visible lesions was confirmed in liver and kidney photomicrographs of rats administered 27.2 mg/kg. These data revealed that administration of Artecxin even at below, therapeutic and over dose could induce mitochondrial mediated apoptosis. The drug tends to predispose mitochondria to non‐responsiveness to inhibitors of MMPT pore opening and apoptosis.