Mechanisms of toxicity ofCleistanthus collinus: Vacuolar ATPases are a putative target

Abstract

Ingestion of Cleistanthus collinus, a shrub native to South India, either intentionally or accidentally, is a common cause of death in the area. Consumption of a boiled decoction of leaves is highly toxic, but medical management of patients is mainly supportive because the molecular mechanisms of toxin action are unknown. Distal renal tubular acidosis is one of the symptoms of poisoning in patients and adenosine triphosphate (ATP) requiring proton pumps is important for acid secretion in the kidney. Hence, we hypothesized that these may be putative targets for C. collinus action and we tested this by exposing rat renal brush border membrane (BBM) as well as cultured kidney cells to a boiled decoction of C. collinus. Exposure to the C. collinus decoction resulted in significant inhibition of vacuolar type H(+)-ATPase (V-ATPase) activity in renal BBM as well as blocking of the proton pump in renal BBM vesicles. C. collinus decoction was also found to inhibit acidification of intracellular organelles in cells in culture, similar to the effect seen with either bafilomycin or concanamycin - specific inhibitors of the V-ATPase. This was accompanied by a decrease in V-ATPase activity, but an increase in protein levels. These results demonstrate that the V-ATPase in renal cells is a putative target for the toxins in C. collinus and the inhibition of this important proton pump probably plays a role in the development of distal renal tubular acidosis and subsequent renal failure seen in poisoned patients.

A clinical study of renal tubular dysfunction inCleistanthus collinus(Oduvanthalai) poisoning

“…The universal occurrence and persistence of metabolic acidosis and the correlation of metabolic abnormalities to clinical outcome, suggests that renal injury is a significant component of the Cleistanthus Collinus toxicity profile. Toxin mediated inhibition of the vacuolar H + ATPase activity in the renal brush border membrane appears to be the underlying mechanism of injury 14. In animal models it was hypothesized that these toxins caused a depletion/inhibition of thiol/thiol dependent enzymes with subsequent loss of ATPase activity 15.…”

Fatal Cleistanthus collinus Toxicity: A Case Report and Review of Literature

“…One study concluded that the active principles of C. collinus inhibit proton pumps in the renal brush border but does not inhibit the Na + ‐K + pump activity . Another recent experimental study on rats opined that inhibition of vacoular type H + ‐ATPase (V‐ATPase) activity in renal brush border membrane (BBM) is responsible for the development of distal renal tubular acidosis (RTA) and subsequent renal failure .…”

“…One report recommended administration of intravenous neostigmine (0.5 mg) in myasthenic crisis‐like syndrome . Another study opined that therapeutic strategies to bypass the inhibition of vacoular ATPase in the renal BBM would have beneficial effects in the clinical management of these patients .…”

“…All parts of the plant are poisonous and extracts from various parts have yielded different toxic compounds . The toxicity of C. collinus is ascribed to the presence of arylnaphthalene lignan lactone glycosides which include cleistanthin A, cleistanthin B, collinusin, and diphyllin .…”

Role of biomarkers of nephrotoxic acute kidney injury in deliberate poisoning and envenomation in less developed countries

“…Glycosides in Cleistanthus inhibit vacuolar H + ATPase in the renal tubular brush border membrane. These glycosides also deplete glutathione and ATPases in renal cells which may cause oxidation of thiol groups resulting in cellular injury .…”