Toxicity and Antigenotoxic Effect of Hispolon Derivatives: Role of Structure in Modulating Cellular Redox State and Thioredoxin Reductase
| Autor: | Beena G. Singh, Atanu Barik, Pogakula Chethna, Neduri V. Balaji, Modukuri V. Ramani, Amit Kunwar, Shruti S. Iyer, K. Indira Priyadarsini, Gottumukkala V. Subbaraju, Vishwa V. Gandhi |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification General Chemical Engineering Chinese hamster ovary cell Hispolon Thioredoxin reductase General Chemistry Pyrazole Article lcsh:Chemistry 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Enzyme lcsh:QD1-999 chemistry Biochemistry Docking (molecular) 030220 oncology & carcinogenesis Toxicity Cytotoxicity |
| Zdroj: | ACS Omega ACS Omega, Vol 3, Iss 6, Pp 5958-5970 (2018) |
| ISSN: | 2470-1343 |
| Popis: | Hispolon (HS), a bioactive polyphenol, and its derivatives such as hispolon monomethyl ether (HME), hispolon pyrazole (HP), and hispolon monomethyl ether pyrazole (HMEP) were evaluated for comparative toxicity and antigenotoxic effects. The stability of HS derivatives in biological matrices followed the order HS < HP ≈ HME < HMEP. The cytotoxicity analysis of HS derivatives indicated that HP and HMEP were less toxic than HS and HME, respectively, in both normal and tumor cell types. The mechanisms of toxicity of HS and HME involved inhibition of thioredoxin reductase (TrxR) and/or induction of reductive stress. From the enzyme kinetic and docking studies, it was established that HS and HME interacted with the NADPH-binding domain of TrxR through electrostatic and hydrophobic bonds, resulting in inhibition of the catalytic activity. Subsequently, treatment with HS, HP, and HMEP at a nontoxic concentration of 10 μM in Chinese Hamster Ovary (CHO) cells showed significant protection against radiation (4 Gy)-induced DNA damage as assessed by micronuclei and γ-H2AX assays. In conclusion, the above results suggested the importance of phenolic and diketo groups in controlling the stability and toxicity of HS derivatives. The pyrazole derivatives, HP and HMEP, may gain significance in the development of functional foods. |
| Databáze: | OpenAIRE |
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