Abstract
Natural phenolic compounds are known to be metabolized by phase II metabolic reactions. In this study, we examined the in vitro sulfation of the main constituents of silymarin, an herbal remedy produced from the fruits of the milk thistle. The study focused on major flavonolignan constituents, including silybin A, silybin B, isosilybin A, isosilybin B, silychristin, and silydianin, as well as the flavonoid taxifolin. Using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS), individual flavonolignans and taxifolin were found to be sulfated by human liver and human intestinal cytosols. Moreover, experiments with recombinant enzymes revealed that human sulfotransferases (SULTs) 1A1*1, 1A1*2, 1A2, 1A3, 1B1, 1C4, and 1E1 catalyzed the sulfation of all of the tested compounds, with the exception of silydianin, which was not sulfated by SULT1B1 and SULT1C4. The sulfation products detected were monosulfates, of which some of the major ones were identified as silybin A 20-O-sulfate, silybin B 20-O-sulfate, and isosilybin A 20-O-sulfate. Further, we also observed the sulfation of the tested compounds when they were tested in the silymarin mixture. Sulfates of flavonolignans and of taxifolin were produced by incubating silymarin with all of the above SULT enzymes, with human liver and intestinal cytosols, and also with human hepatocytes, even though the spectrum and amount of the sulfates varied among the metabolic models. Considering our results and the expression patterns of human sulfotransferases in metabolic tissues, we conclude that flavonolignans and taxifolin can potentially undergo both intestinal and hepatic sulfation, and that SULTs 1A1, 1A3, 1B1, and 1E1 could be involved in the biotransformation of the constituents of silymarin.
Highlights
Silymarin is an herbal hepatoprotective remedy produced from the fruits of the milk thistle (Silybum marianum)
Using available standards of sulfated flavonolignans, we identified silybin A 20-O-sulfate, silybin B 20-O-sulfate, and isosilybin A 20-O-sulfate to be produced as the main sulfates of the respective parent flavonolignans by certain SULT enzymes, and by human liver and intestinal cytosols (Table 1)
We have demonstrated for the first time the sulfation of the main silymarin constituents by human cytosolic sulfotransferases
Summary
Silymarin is an herbal hepatoprotective remedy produced from the fruits of the milk thistle (Silybum marianum). Silymarin are Research supposedwork to undergo bioconversion by intestinal microbiota [6,7],In or the they human organism, silymarin constituents are supposed to undergo bioconversion by intestinal can be absorbed and metabolized in tissues such as the intestine and liver [8]. The biotransformation microbiota [6,7], or they can be absorbed and metabolized in tissues such as the intestine and liver processes in human tissues include two types of reactions, classified as phase I (functionalization) and [8]. The biotransformation processes in human tissues include two types of reactions, classified as phase II (conjugation) reactions. It has been demonstrated that individual silymarin flavonolignans may phase I biotransformation are cytochromes P450 (CYPs) [9]. It has been demonstrated that be demethylated or hydroxylated by one or more human recombinant CYP enzymes, namely CYPs individual silymarin flavonolignans may be demethylated or hydroxylated by one or more human
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