Khat (Catha edulis) Induces Reactive Oxygen Species and Apoptosis in Normal Human Oral Keratinocytes and Fibroblasts

Abstract

Khat chewing is widely practiced in Eastern Africa and the Middle East. Khat is genotoxic to cells within the oral mucosa, and several studies have suggested an association between khat use and oral lesions like hyperkeratosis and oral cancer. This study investigated the mechanism of khat-induced cytotoxicity using primary normal human oral keratinocytes (NOK) and fibroblasts (NOF). Khat induced rounding up of cells, plasma membrane blebbing, and condensation of nuclear chromatin within 3-6 h of exposure. The cells also showed externalization of phosphatidylserine and fragmentation of DNA. Morphological and biochemical features were compatible with cell death by apoptosis. Khat also induced an increase in cytosolic reactive oxygen species (ROS) and a depletion of intracellular glutathione (GSH) within 1 h of exposure. Antioxidants reduced ROS generation, GSH depletion and delayed the onset of cytotoxicity in both cell types. Generally, NOF cells were more sensitive to khat-induced cytotoxicity than NOK cells. These effects were elicited at concentrations of khat expected to occur in the oral cavity during khat chewing. In summary, khat induced apoptotic cell death in primary normal oral keratinocytes and fibroblasts by an early effect on mechanisms that regulate oxidative stress.

Effect of Daily Chewing Soft Buds and Leaves of Catha edulis (Khat) on the Antioxidant Defense System and Oxidative Stress Markers in Blood

“…Our result confirms the previously reported studies, which exhibits the depletion of GSH in long-term Khat chewers or experimental animals treated with Khat extract [17,30]. This enhancing the idea that GSH is strong cellular antioxidants, which effectively scavenges reactive oxygen species (e.g., hydroxyl radical, lipid peroxyl radical and H 2 O 2 ) and other free radicals directly and indirectly through enzymatic reactions [38].…”

“…This result confirms the similar elevation of MDA induced by Khat [16,17,30,41]. Elevation level of MDA reflects the lipid peroxidation that occurred by radicals, from a polyunsaturated lipid abundant in the cell membranes, and this amplifies the damage of cell membrane.…”

“…On the other hand, the flavonoid fraction of the Khat enhances the activity of the antioxidant enzymes in rats and this could provide a protection against the oxidative stress [16]. Khat induces an increase in ROS and a depletion of intracellular glutathione in the cell cultures of human keratinocytes and fibroblasts, the reactions that could be opposed by addition of exogenous antioxidants [17]. Recently, it is reported that chewing Khat inhibits ROS scavenging enzymes in the human blood serum, resulting in significant elevations in free radical loads, which cause the increase in oxidative stress [18,19].…”

Letter by Aleryani and Al-akwa Regarding Article, “Acute Coronary Syndrome and Khat Herbal Amphetamine Use: An Observational Report”

“…Second, khat-induced oxidative stress and apoptosis has also been observed by other researchers. 5 Both observations 2,5 are consistent with short-and long-term genotoxic and cardiac effects on khat chewers. We strongly believe that future studies should also focus on finding a link between pesticide exposure and acute coronary syndrome complications.…”

Qat Chewing and Risk of Potentially Malignant and Malignant Oral Disorders: A Systematic Review

“…32 When exposed to a higher concentration of Qat the oral fibroblasts and keratinocytes underwent programmed cell death in a process involving reactive oxygen species. 33 Moreover, the study also found that oxidative stress can occur in oral cells exposed to Qat. If this occurs in vivo, it could lead to a host of cellular and tissue responses such as increased or decreased proliferation, increased keratotic differentiation and damage to macromolecules like DNA.…”