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Effect of antimalarial drugs on rat enterocyte mitochondrial phospholipase D activity
M Madesh1, K A Balasubramanian
1Department of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore, India.
Abstract:
We have earlier shown that enterocyte mitochondria contain a phospholipase D (PLD) activity which can be stimulated by oxygen free radicals, divalent cations and polyamines. The functional significance of this enzyme in mitochondria is not known but it can be investigated using selective inhibitors. In the present study, mitochondrial PLD was activated by exposure to oxidants (X+XO or menadione), calcium or polyamines and the effect of antimalarial drugs, chloroquine, amodiaquin and primaquine on PLD activity was studied. Chloroquine and amodiaquine inhibited Ca2+ stimulated PLD activity in dose dependent manner whereas these drugs had no significant effect on PLD activated by oxidants or polyamines. Increasing the calcium concentration relieved the PLD inhibition by these drugs. Primaquine did not have any effect on calcium stimulated PLD activity whereas it slightly activated the enzyme. These results indicate that chloroquine and amodiaquine may bind with calcium making it unavailable for PLD activation.
Insights
Antimalarial drugs chloroquine and amodiaquine inhibit calcium-stimulated phospholipase D (PLD) in enterocyte mitochondria. These drugs may work by chelating calcium, impacting mitochondrial function.
Area of Science:
- Mitochondrial biochemistry
- Pharmacology
Background:
- Enterocyte mitochondria possess phospholipase D (PLD) activity.
- PLD can be activated by oxidants, divalent cations, and polyamines.
- The precise function of mitochondrial PLD remains unclear.
Purpose of the Study:
- To investigate the effect of antimalarial drugs on mitochondrial PLD activity.
- To explore the potential mechanism of PLD inhibition by these drugs.
Main Methods:
- Mitochondrial PLD was activated using oxidants, calcium, or polyamines.
- The inhibitory effects of chloroquine, amodiaquine, and primaquine on PLD activity were assessed.
- Dose-dependent inhibition and the impact of varying calcium concentrations were analyzed.
Main Results:
- Chloroquine and amodiaquine demonstrated dose-dependent inhibition of calcium-stimulated PLD.
- These drugs did not significantly affect PLD activated by oxidants or polyamines.
- Increased calcium concentrations reversed the inhibitory effects of chloroquine and amodiaquine.
- Primaquine showed no significant effect or slight activation of calcium-stimulated PLD.
Conclusions:
- Chloroquine and amodiaquine likely inhibit mitochondrial PLD by binding to calcium, thus reducing its availability for enzyme activation.
- This interaction suggests a potential mechanism for how these antimalarial drugs might influence cellular processes involving mitochondrial calcium signaling.