Khat (Catha edulis) generates reactive oxygen species and promotes hepatic cell apoptosis via MAPK activation

Abstract

A number of studies have suggested an association between khat (Catha edulis) chewing and acute liver lesions or chronic liver disease. However, little is known about the effects of khat on hepatic cells. In the current study, we investigated the mechanism behind khat-induced apoptosis in the L02 human hepatic cell line. We used cell growth inhibition assay, flow cytometry and Hoechst 33258 staining to measure hepatocyte apoptosis induced by khat. Western blot analysis was used to detect the expression levels of caspase-8 and -9, as well as those of Bax and Bcl-2. We also measured reactive oxygen species production. The results indicated that khat induced significant hepatocyte apoptosis in L02 cells. We found that khat activated caspase-8 and -9, upregulated Bax protein expression and downregulated Bcl-2 expression levels, which resulted in the coordination of apoptotic signals. Khat-induced hepatocyte apoptosis is primarily regulated through the sustained activation of the c-Jun NH2-terminal kinase (JNK) pathway and only partially via the extracellular signal-regulated kinase (ERK) cascade. Furthermore, the khat-induced reactive oxygen species (ROS) production and the activation of the ROS scavenger, N-acetyl-L-cysteine (NAC), attenuated the khat-induced activation of JNK and ERK. Our results demonstrate that khat triggers the generation of intracellular ROS and sequentially induces the sustainable activation of JNK, which in turn results in a decrease in cell viability and an increase in cell apoptosis.

Khat chewing increases the risk for developing chronic liver disease: A hospital‐based case–control study

“…Rodents given diets containing uncontaminated khat leaves showed elevated liver enzymes and necroinflammatory change on histology, supporting the contention that the natural substances contained in khat leaves are responsible for the hepatic injury . Finally, khat has been shown to trigger generation of reactive oxygen species in human cells in vitro , resulting in hepatocyte apoptosis . Similar histological features have been described in humans following ingestion of ecstasy, another amphetamine‐related drug …”

Khat chewing and cirrhosis in Somaliland: Case series

“…18 Abid demonstrated a biochemical pathway for khat-induced liver damage on human liver cells. 19 The studies cited above of Somali immigrants to Western countries showed that khat is associated with acute and chronic liver disease in humans, including autoimmune hepatitis. Four of our patients improved clinically after stopping khat consumption, and this improvement has been documented in other studies.…”

Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) Signaling Regulates Mitochondrial Biogenesis and Respiration via Estrogen-related Receptor α (ERRα)

“…By acting as both mutagens and mitogens, ROS is capable of inducing oncogenic transformation and promoting carcinogenesis and is proposed to play major roles in tumor cell transformation, progression, and metastasis (10). Growth factor and mitogenic signals that promote cancer cell growth and survival have been linked to altered mitochondrial functions and generation of ROS (11)(12)(13)(14)(15)(16). However, the molecular mechanism of whether and how the aberrant growth factor/mitogenic signals in tumor cells may control mitochondrial mass and respiration still remains unclear.…”