The sub-acute toxicity of kavalactone in rats: a study of the effect of oral doses and the mechanism of toxicity in combination with ethanol

Abstract

Kava is a herbal supplement and beverage made from the Piper methysticum plant, which is known for its recreational use as a mood enhancer, relaxation, as well as pain relief for centuries. Kava is widely used among alcoholics, but it is dangerous and potentially fatal. The objectives of this study were to examine the sub-acute toxicity effects of different doses of 70% kavalactone (KL) in rats by oral application, as well as to elucidate the mechanisms of toxicity alone and in combination with ethanol (EtOH). The most common side effects observed were abnormal breathing, ataxia, lethargy, loss of appetite, indigestion, and loss of coordination, especially in the 800 mg/kg bw, po bodyweight dosage of kava treatment group alone, and in combination with EtOH. In the sub-acute study, there were dose-related decreases in body weight, feed intake, and water consumption rates. Gross and histopathological findings revealed that the liver was abnormal in color, size, consistency, and the weight significantly increased at a dose of 800 mg/kg bw, po, with KL alone and a greater increase in combination with EtOH. Hepatocellular hypertrophy (HP) and necrosis with Kupffer cells hyperplasia were observed in the periacinar zone of all rats dosed with KL (800 mg/kg bw, po) alone, and extensive changes were observed in combination with EtOH. The periportal (Z1) and mid-zonal (Z2) areas of hepatocytes were less affected as compared to the periacinar zone. These results demonstrate that EtOH exacerbated the sedative and hypnotic activity of KL, and markedly increased toxicity. The histopathological results supported the clinical and biochemical findings and the severity of hepatic damage in a dose-dependent manner.

Keywords:

• Kavalactone
• sub-acute toxicity
• morphological changes
• blood biochemistry
• rat model

Acknowledgements

The authors are grateful to the Department of Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia, for the providing of laboratory facilities, technical knowledge, and assistance for this study.

Ethical approval

The protocol of the study was approved by the Animal Care and Use Committee (ACUC), Faculty of Veterinary Medicine, UPM (UPM/IACUC/AUP- R082/2015). All animals received careful handling, following the guidelines outlined by the ACUC.

Author contributions

Conceptualization: Mohammed Abdulabbas Hasan, Syam Mohan, and Heshu Sulaiman Rahman; methodology: Mohammed Abdulabbas Hasan, Syam Mohan, Heshu Sulaiman Rahman, Hemn Hasan Othman, and Abdullah Farasani; writing and editing: Hemn Hasan Othman and Shirwan Hamasalih Omer; project administration: Mohammed Abdulabbas Hasan and Abdullah Farasani; and funding acquisition: Mohammed Abdulabbas Hasan. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This research was funded by ARUGS, grant number 5450334.