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ToxSci Advance Access originally published online on February 29, 2008
Toxicological Sciences 2008 103(2):311-324; doi:10.1093/toxsci/kfn044
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Ochiba M. Lukandu*,{dagger}, Daniela E. Costea*, Evelyn Neppelberg{ddagger}, Anne C. Johannessen*,§ and Olav K. Vintermyr§,*,1

* Section for Pathology, The Gade Institute {dagger} Centre for International Health {ddagger} Department of Clinical Dentistry § Department of Pathology, The Gade Institute, Haukeland University Hospital, University of Bergen, Bergen, Norway

1 To whom correspondence should be addressed at Department of Pathology, The Gade Institute, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway. Fax: +47-55-97-3158. E-mail: Olav.Vintermyr{at}helse-bergen.no.

Received November 12, 2007; accepted February 26, 2008


  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.

Key Words: khat; oral keratinocytes; oral fibroblasts; reactive oxygen species; apoptosis.


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