ABSTRACT
Amiodarone, a cationic amphiphile known for its clinical efficacy as an antiarrhythmic agent, unfortunately causes serious side effects. The present study was undertaken to investigate its intestinal toxicity, on oral administration, using a Wistar rat model. The relationship of drug dose and duration on intestinal toxicity was investigated. Optimum changes were observed after 21 days of AD administration at a dose of 175 mg/Kg body wt/day and this dosage was used for further studies. Histological studies revealed decreased villi and crypt size and reduction in the cellularity of lamina propria. Marked reduction in the activities of Ca(2+)-ATPase, alkaline phosphatase, disaccharidases and Na+, K(+)-ATPase was observed. The reduction in the uptake of 14C-glucose and 14C-glycine, in vivo, was correlated to the reduction in the activities of these enzymes. The reduction in the activities of the intestinal membrane bound enzymes may be attributed to altered morphology of the villi and crypts.
Subject(s)
Alkaline Phosphatase/metabolism , Amiodarone/toxicity , Anti-Arrhythmia Agents/toxicity , Calcium-Transporting ATPases/metabolism , Intestine, Small/drug effects , Sodium-Potassium-Exchanging ATPase/metabolism , Animals , Disaccharidases/metabolism , Intestinal Mucosa/drug effects , Intestinal Mucosa/enzymology , Intestine, Small/enzymology , Male , Microvilli/drug effects , Microvilli/enzymology , Rats , Rats, WistarABSTRACT
The chemoprotection extended by eugenol against carbon tetrachloride (CCl4) intoxication was established by studies on drug-metabolizing phase I and phase II enzymes. An overall decrease in drug-metabolizing enzymes, namely NADPH-cytochrome c reductase, NADH-cytochrome reductase, coumarin hydroxylase, 7-ethoxy coumarin-O-deethylase, UDP-glucuronyltransferase and glutathione-S-transferase, was observed with CCl4 intoxication, with a subsequent decrease in cytochrome P450 and cytochrome b5 content. CCl4 caused a significant decrease in microsomal phospholipids and the marker enzymes glucose-6-phosphatase and 5'-nucleotidase, and an increase in thiobarbituric acid reactive substances (TBARS). Simultaneous administration of eugenol with CCl4 inhibited the accumulation of TBARS and the decrease in the microsomal phospholipids and marker enzymes. Further, the chemical onslaught imposed by CCl4 on the drug-metabolizing system was removed successfully by eugenol. Eugenol appears to act as an in vivo antioxidant and as a better inducer of phase II enzymes than phase I enzymes. It is therefore suggested that eugenol could be an interesting basic structure for drug design.
Subject(s)
Antioxidants/pharmacology , Aryl Hydrocarbon Hydroxylases , Carbon Tetrachloride Poisoning/enzymology , Eugenol/pharmacology , Liver/drug effects , 5'-Nucleotidase/analysis , 7-Alkoxycoumarin O-Dealkylase/analysis , Animals , Cytochrome P-450 CYP2A6 , Cytochrome P-450 Enzyme System/analysis , Cytochrome Reductases/analysis , Cytochrome-B(5) Reductase , Glucose-6-Phosphatase/analysis , Liver/enzymology , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Mixed Function Oxygenases/analysis , NADH Dehydrogenase/analysis , Phospholipids/metabolism , Rats , Rats, Wistar , Thiobarbituric Acid Reactive SubstancesABSTRACT
Chloroquine causes an increase in phospholipid and a decrease in cholesterol in liver mitochondria. A significant decrease in the activities of mitochondrial inner membrane enzymes such as NADH dehydrogenase, succinate dehydrogenase and cytochrome c oxidase is observed. Decrease in cytochrome contents and respiratory control ratio, shown by a decrease in state 3(+ADP) and an increase in state 4 (-ADP), implies decreased ATP synthesis following chloroquine administration. The results confirm drug-induced inhibition of mitochondrial respiration, thereby impairing availability and utilisation of energy.
