Isoform-specific therapeutic control of sulfonation in humans.
Isoform-specific therapeutic control of sulfonation in humans.
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DOI：
10.1016/j.bcp.2018.11.010
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发表时间：
2019-01
影响因子：
5.8
通讯作者：
Leyh TS
中科院分区：
文献类型：
--
作者：
Cook I;Wang T;Leyh TS
数百种，甚至数千种代谢物的活性由人胞质硫转移酶（SULTs）调控，SULTs是一个由13个成员组成的疾病相关酶家族，催化硫酰基部分（- so3）从3 ' -磷酸腺苷5 ' -磷酸磺酸盐转移到受体的羟基和胺。SULTs含有两个独立的变构位点，其中一个是本研究的重点，与非甾体抗炎药（NSAIDs）结合。第一个非甾体抗炎药结合位点SULT1A1的结构最近被阐明，同源性模型表明该位点的变体存在于所有SULT亚型中。当前研究的目的是评估非甾体抗炎药结合位点是否可以以一种特定的方式调节人类硫酰基转移。Mefenamic acid （Mef）是一种有效的（Ki 27 nM） SULT1A1的nsaid抑制剂，SULT1A1是小肠和肝脏中主要的SULT亚型。对乙酰氨基酚（APAP）是一种SULT1A1特异性底物，在人体中广泛磺化。脱氢表雄酮（DHEA）对SULT2A1是特异性的，我们在这里表明它对Mef抑制不敏感。尿中APAP和DHEA磺酸盐很容易被量化，因此Mef对APAP和DHEA磺酸盐的影响可以无创地研究。这些化合物以单一治疗剂量口服给具有典型apap代谢物谱的健康成年男性。Mef在第一次代谢过程中显著降低APAP的磺化，并在不影响脱氢表雄酮磺化的情况下显著降低全身APAP的磺化；因此，非甾体抗炎药位点似乎可以以特定的方式控制人类磺化。
The activities of hundreds, perhaps thousands, of metabolites are regulated by human cytosolic sulfotransferases (SULTs) – a 13-member family of disease relevant enzymes that catalyze transfer of the sulfuryl moiety (-SO3) from PAPS (3′-phosphoadenosine 5′-phosphosulfonate) to the hydroxyls and amines of acceptors. SULTs harbor two independent allosteric sites, one of which, the focus of this work, binds non-steroidal anti-inflammatory drugs (NSAIDs). The structure of the first NSAID-binding site – that of SULT1A1 – was elucidated recently and homology modeling suggest that variants of the site are present in all SULT isoforms. The objective of the current study was to assess whether the NSAID-binding site can be used to regulate sulfuryl transfer in humans in an isoform specific manner. Mefenamic acid (Mef) is a potent (Ki 27 nM) NSAID-inhibitor of SULT1A1 – the predominant SULT isoform in small intestine and liver. Acetaminophen (APAP), a SULT1A1 specific substrate, is extensively sulfonated in humans. Dehydroepiandrosterone (DHEA) is specific for SULT2A1, which we show here is insensitive to Mef inhibition. APAP and DHEA sulfonates are readily quantified in urine and thus the effects of Mef on APAP and DHEA sulfonation could be studied non-invasively. Compounds were given orally in a single therapeutic dose to a healthy, adult male human with a typical APAP-metabolite profile. Mef profoundly decreased APAP sulfonation during first pass metabolism and substantially decreased systemic APAP sulfonation without influencing DHEA sulfonation; thus, it appears the NSAID site can be used to control sulfonation in humans in a SULT-isoform specific manner.
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影响因子：
4.1
作者：
HOFFMANN, KJ;AXWORTHY, DB;BAILLIE, TA
通讯作者：
BAILLIE, TA
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DOI：
10.1038/labinvest.2015.84
发表时间：
2015-09
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
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作者：
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通讯作者：
Gao CF
DOI：
10.1073/pnas.1613913113
发表时间：
2016-12-13
影响因子：
11.1
作者：
Cook, Ian;Wang, Ting;Leyh, Thomas S.
通讯作者：
Leyh, Thomas S.
DOI：
10.1111/j.1365-2125.1992.tb04112.x
发表时间：
1992-07-01
影响因子：
3.4
作者：
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通讯作者：
GAUCHER, A
影响因子：
4.8
作者：
Cook, Ian;Wang, Ting;Leyh, Thomas S.
通讯作者：
Leyh, Thomas S.