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Genotoxicity assessment of andrographolide. / Yusrizam Sharifuddin

Swansea University Author: Yusrizam Sharifuddin

Abstract

In this thesis, the genotoxic potential of andrographolide, which is a primary phytochemical of an annual herb Andrographis paniculata, was assessed and the possible mechanisms of action were elucidated. In silico predictions showed that andrographolide may be capable of inducing skin sensitisation...

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Published: 2008
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa42296
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Abstract: In this thesis, the genotoxic potential of andrographolide, which is a primary phytochemical of an annual herb Andrographis paniculata, was assessed and the possible mechanisms of action were elucidated. In silico predictions showed that andrographolide may be capable of inducing skin sensitisation and chromosome damage in mammals in vitro and the identification of possible metabolites. Andrographolide was demonstrated to induce micronuclei formation in vitro in three cell lines tested namely AHH-1, MCL-5 and V-79. In AHH-1 and V-79 cell lines, the highest frequency of micronuclei was recorded at 30 muM whereas in MCL-5 cell line, 50 p,M of the compound was necessary to elicit similar damage, which may be due differences in cellular metabolism capacity. The phytochemical was shown to cause dose-dependent cellular cytotoxicity in all the cell lines tested with cells dying primarily via necrosis compared to apoptosis and effectively reduced cell number. Kinetochore labelling on MCL-5 cells challenged with increasing doses of andrographolide revealed that the phytochemical acts in aneugenic manner evident from the increment in kinetochore-positive micronuclei. The compound of interest was also found to disrupt segregation fidelity via centrosome amplification resulting in chromosomal aberration. The presence of extra microtubule organising centres may play a role in the promotion of aberrant mitoses. Disruption to normal cell division was observed even after the removal of the compound in vitro. Mammalian HFRT point mutation assay using AHH-1 cell line revealed that andrographolide induced mutation evident from HPRT- mutant colonies formation between 5muM and 30muM. The phytochemical was also found to exert cytotoxicity in a concentration-dependent manner between 1muM and 50muM. Thus, andrographolide is capable of disrupting normal mammalian cell division and causing dose-dependent cytotoxicity in vitro.
Keywords: Toxicology.
College: Faculty of Medicine, Health and Life Sciences

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