| Budget Amount *help |
¥15,500,000 (Direct Cost: ¥15,500,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2003: ¥10,300,000 (Direct Cost: ¥10,300,000)
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| Research Abstract |
Cytosolic sulfotransferases (SULTs) are generally thought to be involved in the phase II detoxification of xenobiotic compounds as well as homeostasis of endogenous compounds. The SULTs play important role in sulfation in vivo, therefore the SULTs are presented in variety animals such as human and fish. Recently, it is reported that mammalian SULTs play a role in metabolism of environmental estrogens in nature. In fact, it is reported that human SULTs catalyze to sulfate environmental estrogens. Otherwise, fishes are directly exposed to environmental estrogens, however, there has been little information about fish sulfotransferases.
In this work, it was demonstrated that several representative environmental estrogens such as bisphenol A and flavonoids including estrogen were sulfated by zebrafish cytosolic SULTs. Results showed that the enzyme, designated SULT1 ST #2, displayed high activities toward estrone (E_1) and 17β-estradiol (E_2). This enzyme also displayed high activities towar
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d flavonoids and alkyl phenolic compounds. In addition, several environmental estrogens showed a concentration-dependent inhibition on sulfation to regulate estrogen concentration.
Moreover, it was investigated that human SULTs were influenced by soybeans isoflavone. Final, it is clear that human SULTs were inhibited by various environmental estrogens, therefore, it was investigated the effects of coding single nucleotide polymorphisms (cSNPs) of several SULTs on their enzyme activities and on inhibitory effect on estrogen sulfation. A number of SULT amino acid variants deriving from cSNPs were generated by site-directed mutagenesis, expressed, and purified. In these result, specific activities for 17β-estradiol of hSUL1A1 variant ^*4(A146T, E181G and R213H) and hSUL1E1 variant ^*2(D22Y) were markedly decreased as compared with wild-type enzyme. In addition, there were differences in inhibitory effects of glycitein on E_2 sulfation in the hSULT1E1 wild-type and variant^*4 (P253H).
In summary, these results suggested that environmental estrogens have a capacity of disrupt endocrine-mediated events by inhibiting estrogen sulfation. In human, it is suggested that the functional roles of cytosolic SULTs may be influenced by various factors such as environmental estrogens and cSNPs. Less
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