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Co-oxidation-mediated xenobiotic activation and cytotoxicity by 12-lipoxygenase in intact platelets

Title
Co-oxidation-mediated xenobiotic activation and cytotoxicity by 12-lipoxygenase in intact platelets
Author
배옥남
Keywords
Co-oxidation; Peroxidase-mediated bioactivation; Cytotoxicity; α-Naphthol; Reactive metabolite; Lipoxygenase; Prostaglandin H synthase; Platelets
Issue Date
2008-04
Publisher
ELSEVIER IRELAND LTD
Citation
TOXICOLOGY, v. 247, No. 2-3, Page. 154-160
Abstract
Peroxidase-mediated co-oxidation process has been suggested as a major alternative pathway for xenobiotic bioactivation other than hepatic cytochrome P450 monooxygenase system. Despite the wealth of reports on the possible involvement of co-oxidation in bioactivation of various compounds, clear manifestation of co-oxidation-mediated xenobiotic bioactivation in intact cell system without extra sources of peroxidase system has been difficult to demonstrate, mainly due to the natural scarcity of peroxidase activities in fresh intact cells. in the present study, arachidonic acid (AA) dependent bioactivation of a-naphthol, a representative phenolic compound, was demonstrated as shown by covalent binding increases in alpha-naphthol concentration dependent manner in freshly prepared intact platelets, where two AA dependent representative peroxidases, 12-lipoxygenase (12-LOX) and prostaglandin H synthase (PHS) are abundantly expressed. Inhibitors of 12-LOX attenuated the covalent binding of alpha-naphthol while inhibitors of PHS were not effective, indicating the predominant role of 12-LOX in AA-initiated co-oxidation in intact platelets. In addition, free radical scavengers and thiol donors prevented effectively the bioactivation of a-naphthol, suggesting the involvement of naphthoxy radical or naphthoxy-derived radical generation. Notably, the co-oxidation process resulted in enhanced cytotoxicities of alpha-naphthol against platelets indeed, as observed by cellular membrane disturbance and mitochondrial membrane potential decrease. With these results, we believe that an important in vitro evidence of peroxidase-mediated xenobiotic activation was provided for understanding the toxicological implication of peroxidase-mediated co-oxidation in the xenobiotic bioactivation. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
URI
https://www.sciencedirect.com/science/article/pii/S0300483X08001054http://repository.hanyang.ac.kr/handle/20.500.11754/80271
ISSN
0300-483X
DOI
10.1016/j.tox.2008.02.015
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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