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| 1.
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Hayakawa, Kazuichi ; Bekki, Kanae ; Yoshita, Morio ; Tachikawa, Chihiro ; Kameda, Takayuki ; Tang, Ning ; Toriba, Akira ; Hosoi, Shinzo
概要:
Estrogenic and antiestrogenic activities of 19 quinoid polycyclic aromatic hydrocarbons (PAHQs) and 9 ketone PAHs were e
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valuated by the yeast two-hybrid assay using yeast cells expressing estrogen receptor-α (ERα). Binding affinity of PAHQs to ERα was assayed by the polarized fluorescence method using FluormoneTM ES2. Ten PAHQs having 3-5 rings showed antiestrogenic activities. The most strongly antiestrogenic PAHQs were 1,4-chrysenequinone and 5,6-chrysenequinone. On the other hand, benzo[a]pyrene-3,6-quinone showed the strongest estrogenic activity. However, the other compounds tested did not show so strong estrogenic/antiestrogenic activities. Binding affinity to ER was required but not sufficient for estrogenic/antiestrogenic activities of PAHQs. The length-to-breadth ratios of the rectangular planes surrounding the ring molecules and the distances between the oxygen atom of the carbonyl group and farthest hydrogen atom of estrogenic/antiestrogenic PAHQs were in narrow ranges, suggesting a structure-activity relationship. As interactions between active PAHQ and ER, hydrogen bonding between carbonyl groups and amino acid residues and van der Waals forces were considered.
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| 2.
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Kameda, Takayuki ; Akiyama, Ayuko ; Yoshita, Morio ; Tachikawa, Chihiro ; Toriba, Akira ; Tang, Ning ; Hayakawa, Kazuichi
概要:
The mutagenicities and endocrine-disrupting activities of two isomers of mononitrated 1-hydroxypyrene [1-hydroxy-x-nitro
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pyrenes (1-OH-x-NPs); x = 2 and 5], which are not only photoreaction products of 1-nitropyrene (1-NP) but also constituent of ambient airborne particles, were evaluated for the first time using the Ames plate incorporation assay and the yeast two-hybrid assay, respectively. The mutagenicity of 1-OH-5-NP was weakly positive in the absence of rat liver S9, but was enhanced up to 3-fold with the metabolic activation by S9. On the contrary, 1-OH-2-NPdid not exhibit significant mutagenicity in the presence or absence of S9. 1-OH-5-NP showed weak estrogenic activity, but 1-OH-2-NP did not show any estrogenic activity. The concentration of 1-OH-5-NP that gave 10% of activity of 1.0 × 10-6M 17ß- estradiol (E2) was 5.4 × 10-7M. 1-OH-5-NP exhibited stronger antiestrogenic and antiandrogenic activities than 1-OH-2-NP. 1-OH-5-NP at a concentration of 1.0 × 10-6M inhibited 71 and 90%of ß-galactosidase activity induced by 1.0 × 10-9Mof E2 and 1.0 × 10-8M of 5a-dihydrotestosterone (DHT), respectively. On the other hand, 1.0 × 10-6M of 1-OH-2-NP inhibited 16 and 43% of ß-galactosidase activity induced by 1.0 × 10-9M of E2 and 1.0 × 10-8M of DHT, respectively. These findings point out the need for determining the environmental sources and distribution of 1-OH-2-NP and 1-OH-5-NP as well as the other hydroxynitropyrene isomers. © 2011 The Pharmaceutical Society of Japan.
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| 3.
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論文
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Kameda, Takayuki ; Akiyama, Ayuko ; Toriba, Akira ; Tachikawa, Chihiro ; Yoshita, Morio ; Tang, Ning ; Hayakawa, Kazuichi
概要:
Endocrine disrupting activities of three isomers of monohydroxylated 1-nitropyrene (1-NP) [3-, 6-, and 8-hydroxy-1-nitro
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pyrenes (OHNPs)] were evaluated for the first time by yeast two-hybrid assay. OHNPs, which are not only metabolites of 1-NP but are also found in airborne particles, did not exhibit androgenic activity but exhibited estrogenic, antiestrogenic, and antiandrogenic activities. 6-OHNP showed the strongest estrogenic activity among the three OHNP isomers examined in this study. Concentrations of the OHNP isomers that gave 10% of activity of 1.0 × 10-6 M 17β-estradiol (E2) were as follows: 3-OHNP, 6.0 × 10 -7 M; 6-OHNP, 6.0 × 10-8 M; 8-OHNP, 9.0 × 10-7 M. On the contrary, 8-OHNP exhibited the strongest antiestrogenic and antiandrogenic activities of the three isomers. 1.0 × 10-6 M of 8-OHNP inhibited 32 and 90% of β-galactosidase activity induced by 1.0 × 10-9 M of E2 and 1.0 × 10-8 M of 5α-dihydrotestosterone (DHT), respectively. These findings point out the necessity for detailed investigation of environmental sources and distributions of OHNPs as well as the parent 1-NP.
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| 4.
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Hayakawa, Kazuichi ; Onoda, Yu ; Tachikawa, Chihiro ; Hosoi, Shinzo ; Yoshita, Morio ; Chung, Sang Woon ; Kizu, Ryoichi ; Toriba, Akira ; Kameda, Takayuki ; Tang, Ning
概要:
Estrogenic/antiestrogenic activities of 14 polycyclic aromatic hydrocarbons (PAHs) and 63 monohydroxylated PAHs (OHPAHs)
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having 2 to 6 rings were evaluated by yeast two-hybrid assay expressing human estrogen receptor α. Relative effective potencies of estrogenic and antiestrogenic activities were calculated as the inverse values of the relative concentration of the test compound that gave the same activities of E2 and 4-hydroxytamoxifen, respectively. PAHs did not show any estrogenic/antiestrogenic activity, but several OHPAHs having 3 to 5 rings showed activities. Especially, OHPAHs having 4 rings such as 3-, 4- and 10-hydroxybenz[a]anthracenes (3-, 4- and 10-OHBaAs) and 2-hydroxychrysene (2-OHCh) showed strongly estrogenic activity. Several other OHPAHs having 4 rings such as 2- and 3-hydroxybenzo[c]phenanthrenes (2-, 3- OHBcPhs), 2-OHBaA and 3-OHCh showed strongly antiestrogenic activity. The length-to-breadth (L/B) ratios of the rectangular van der Walls planes surrounding the ring molecules of estrogenic OHPAHs were in the narrow range from 1.599 to 1.734. The distances between the oxygen atom of the phenol group and farthest hydrogen atom (O-H distance) of the estrogenic OHPAHs ranged from 10.825 A° to 11.738 A°. The L/B ratios and O-H distances of antiestrogenic OHPAHs were in the wider ranges from 1.277 to 1.734 and from 8.47 A° to 11.681 A°, respectively. The partial charges (atomic unit) of the phenol group of both estrogenic and antiestrogenic OHPAHs were in the range from 0.250 atmic unit (au) to 0.253 au. The similarity of these values to those of E2 and diethylstilbestrol suggested that the compositions of estrogenic OHPAHs were similar to them and that the compositional conditions of estrogenic OHPAHs were much smaller than those of antiestrogenic OHPAHs. These results raise the possibility of predicting the estrogenic/antiestrogenic activities of OHPAHs from their structural characteristics, although using only the above three parameters might not be enough for accurate estimations.
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