Sulfotransferase pharmacogenetics.
Sulfotransferase pharmacogenetics.
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磺基转移酶药物遗传学。
DOI：
10.1016/0163-7258(90)90010-y
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发表时间：
1990
影响因子：
13.5
通讯作者：
Weinshilboum,R
中科院分区：
文献类型：
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作者：
Weinshilboum,R
硫酸盐结合是许多药物、外源化合物和神经递质代谢的重要途径（Dodgson，1977；Roy，1981；Weinshilboum，1986a）。苯酚磺基转移酶（PST，EC 2.8.2.1）是催化药物硫酸化的最重要的酶（Roy，1981；Weinshilboum，1986b）（图1）。尽管外源化合物的硫酸盐结合在一个多世纪前就被首次描述（Baumann，1876），但直到最近才研究了导致这种生物转化途径个体差异的因素，并且遗传在硫酸化调节中的可能作用只是在过去十年中才被评估。通过开发能够测量容易获得的人体组织（血小板）中 PST 活性的灵敏测定法，使硫酸盐结合的药物遗传学研究成为可能（Hart 等人，1979 年；Anderson 和 Weinshilboum，1980 年）。显然，血小板本身通常在药物代谢中不起重要作用。因此，这些研究的假设是血小板中 PST 的生化特性和调节可能反映了药物代谢部位酶的特性和调节。该假设已经过测试并被证明是正确的，至少对于一种形式的 PST 来说是这样。现在已知，遗传在人类 PST 活性个体差异的调节中起着重要作用（Reveley 等，1982，1983；Van Loon 和 Weinshilboum，1984；Price 等，1988），PST 活性的药物遗传学变异与药物硫酸盐结合的个体差异有关（Reiter 和 Weinshilboum，1982a；Bonham-Carter）等人，1983；坎贝尔等人，1985）。随后的讨论将描述我们目前对人体组织中 PST 活性水平和物理性质的遗传调控的理解，以及该酶的遗传调控的药理学后果。然而，为了使该讨论易于理解，有必要简要回顾一下 PST 的生物化学。
Sulfate conjugation is an important pathway in the metabolism of many drugs, xenobiotic compounds and neurotransmitters (Dodgson, 1977; Roy, 1981; Weinshilboum, 1986a). Phenol sulfotransferase (PST, EC 2.8. 2.1) is the most important of the enzymes which catalyze the sulfation of drugs (Roy, 1981; Weinshilboum, 1986b)(Fig. 1). Even though the sulfate conjugation of exogenous compounds was first described more than a century ago (Baumann, 1876), factors responsible for individual variations in this pathway of biotransformation have only been studied recently, and the possible role of inheritance in the regulation of sulfation has only been evaluated during the past decade. Pharmacogenetic studies of sulfate conjugation in humans were made possible by the development of sensitive assays capable of measuring the activity of PST in an easily obtained human tissue, the blood platelet (Hart et al., 1979; Anderson and Weinshilboum, 1980). Obviously, the platelet itself does not usually play a significant role in drug metabolism. Therefore, the hypothesis underlying those studies was that the biochemical properties and regulation of PST in the platelet might reflect the properties and regulation of the enzyme at sites of drug metabolism. That hypothesis has already been tested and shown to be correct, at least for one form of PST. It is now known that inheritance plays a major role in the regulation of individual variations in PST activity in humans (Reveley et al., 1982, 1983; Van Loon and Weinshilboum, 1984; Price et al., 1988), and pharmacogenetic variations in PST activity are related to individual differences in the sulfate conjugation of drugs (Reiter and Weinshilboum, 1982a; Bonham-Carter et al., 1983; Campbell et al., 1985). The subsequent discussion will describe our present understanding of the genetic regulation of the level of activity and physical properties of PST in human tissues as well as the pharmacologic consequences of genetic regulation of the enzyme. However, to make that discussion understandable, it will be necessary to review briefly the biochemistry of PST.