TY - JOUR
T1 - Cytotoxic action mode of a novel porphyrin derivative isolated from harmful red tide dinoflagellate Heterocapsa circularisquama
AU - Kim, Daekyung
AU - Miyazaki, Yousuke
AU - Nakashima, Takuji
AU - Izvashita, Takashi
AU - Fujita, Tsuyoshi
AU - Yamaguchi, Kenichi
AU - Choi, Kwang Sik
AU - Oda, Tatsuya
PY - 2008
Y1 - 2008
N2 - Heterocapsa circularisquama is known to cause lethal effect on bivalves, but toxic effect on fish has not been reported yet. Recently, we have found that H. circularisquama has potent light-dependent hemolytic toxins. Based on the chemical structural analysis, one of the hemolytic toxins named H2-a was found to be a novel porphyrin derivative with similar structure to pyropheophorbide a methyl ester (PME), a well-known photoactive hemolytic agent (Miyazaki et al., Aquatic Toxicol. 2005;73:382-393). To clarify the cytotoxic action mode of H2-a, we examined the effects of H2-a on HeLa cells in comparison with PME. The cytotoxicities of both reagents were strictly light dependent, and no significant cytotoxic effects including cellular morphological changes were induced without light illumination. The dose response curves revealed that H2-a showed stronger cytotoxicity to HeLa cells than PME. Fluorescence microscopic observation suggested that H2-a tends to accumulate in the plasma membrane, whereas PME seems to distribute entire cytoplasm. Although PME induced typical apoptotic nuclear morphological changes and DNA fragmentation in HeLa cells, no such apoptosis-inducing ability of H2-a was observed. Among the radical scavengers, histidine significantly inhibited the cytotoxic activity of H2-a, suggesting the involvement of singlet oxygen in the cytotoxicity. These results suggest that the cytotoxic mechanism of H2-a is necrotic rather than apoptosis differing from PME, even though these are structurally quite similar to each other. The relatively high affinity of H2-a to the plasma membrane might result in the potent and quick cytotoxicity without induction of apoptotic signal transduction.
AB - Heterocapsa circularisquama is known to cause lethal effect on bivalves, but toxic effect on fish has not been reported yet. Recently, we have found that H. circularisquama has potent light-dependent hemolytic toxins. Based on the chemical structural analysis, one of the hemolytic toxins named H2-a was found to be a novel porphyrin derivative with similar structure to pyropheophorbide a methyl ester (PME), a well-known photoactive hemolytic agent (Miyazaki et al., Aquatic Toxicol. 2005;73:382-393). To clarify the cytotoxic action mode of H2-a, we examined the effects of H2-a on HeLa cells in comparison with PME. The cytotoxicities of both reagents were strictly light dependent, and no significant cytotoxic effects including cellular morphological changes were induced without light illumination. The dose response curves revealed that H2-a showed stronger cytotoxicity to HeLa cells than PME. Fluorescence microscopic observation suggested that H2-a tends to accumulate in the plasma membrane, whereas PME seems to distribute entire cytoplasm. Although PME induced typical apoptotic nuclear morphological changes and DNA fragmentation in HeLa cells, no such apoptosis-inducing ability of H2-a was observed. Among the radical scavengers, histidine significantly inhibited the cytotoxic activity of H2-a, suggesting the involvement of singlet oxygen in the cytotoxicity. These results suggest that the cytotoxic mechanism of H2-a is necrotic rather than apoptosis differing from PME, even though these are structurally quite similar to each other. The relatively high affinity of H2-a to the plasma membrane might result in the potent and quick cytotoxicity without induction of apoptotic signal transduction.
KW - Apoptosis
KW - Cytotoxicity
KW - Heterocapsa circularisquama
KW - Photosensitizing agent
KW - Porphyrin derivative
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U2 - 10.1002/jbt.20216
DO - 10.1002/jbt.20216
M3 - Article
C2 - 18561331
AN - SCOPUS:46849104266
VL - 22
SP - 158
EP - 165
JO - Journal of Biochemical and Molecular Toxicology
JF - Journal of Biochemical and Molecular Toxicology
SN - 1095-6670
IS - 3
ER -