| Summary: | 博士 === 國立中興大學 === 食品科學系 === 93 === Abstract
Sulfation (sulfonation) is one of the major phase II conjugative reactions involved in the biotransformation of various endogenous compounds, drugs, and xenobiotics as well as in steroid biosynthesis, catecholamine metabolism, and thyroid hormone homeostasis. Phenolic acids such as hydroxybenzoic acids and hydroxycinnamic acids are antioxidant compounds in fruits and vegetables. Research on phenolic acids is of current interest due to the important biological and pharmacological properties attributed to their antioxidant properties. Therefore, the objective of this study was to investigate the effect of dietary polyphenolic compounds on human sulfotransferase. There are six topics included in this study: (1) Effect of phenolic Acid on human phenolsulfotransferases in relation to their antioxidant activity (2) Synergistic effect of antioxidant phenolic acids on human phenolsulfotransferase activity (3) Effect of vegetables on human phenolsulfotransferases in relation to their antioxidant activity and total phenolics (4) Induction of phenolsulfotransferase expression by antioxidant phenolic acids in human hepatoma HepG2 cells (5) Modulation of hepatic phase II phenolsulfotransferase and antioxidant status by phenolic acids in rats. (6) Cytoprotective effects of P-form phenolsulfotransferase induction by phenolic acid
Our studies revealed that (1) p-hydroxybenzoic acid, gallic acid, gentisic acid, ferulic acid, and p-coumaric acid all could increase the activities of both PST-P and PST-M. These phenolic acids also possessed antioxidant capacity in the ORAC and TEAC assays. (2) Furthermore, in both two-compound and three-compound combinations with each of other phenolic acids, gallic acid and gentistic acid exhibit the potential synergistic effects in the promotion of PSTs activities. The overall effects of phenolic acids on the activities of PST-P and PST-M are highly correlated to their ORAC values, suggesting that antioxidant phenolic acids might alter sulfate conjugation. (3) Moreover, the PST-P activity was significantly induced by asparagus, broccoli, cauliflower, celery, and eggplant, whereas PST-M activity was induced by asparagus, broccoli, carrot, eggplant, and potato at a concentration of 100 g/ml. The major polyphenols in broccoli, the most potential inducer in both forms of PSTs activities, was antioxidant phenolic acids. HPLC retention times and standard spiked indicated the presence of gallic acid, p-hydroxybenzoic acid, p-coumaric acid, gentisic acid, and ferulic acid in broccoli. These results imply that vegetables have a capability of inducing PST activity, and the PST induction may be possibly ascribed to antioxidant phenolic acids in vegetable extracts. (4) Furthermore, human hepatoma cell line HepG2 was used as a model to investigate the effect of antioxidant phenolic acids on enzymatic activity and expression of one of the major phase II sulfateconjugation enzymes, PST-P. The results showed that gallic acid, gentisic acid, p-hydroxybenzoic acid, and p-coumaric acid were found to increase the PST-P activity in a dose-dependent manner. A significant correlation between the expressions of PST-P mRNA and the corresponding PST-P activity was observed. The results demonstrated that certain antioxidant phenolic acids could induce PST-P activity in HepG2 cells by promoting PST-P mRNA and protein expression, suggesting a novel mechanism by which antioxidant phenolic acids may be implicated in phase II sulfate conjugation. (5) Used the animal models to investigate the the modulatory effect of phenolic acids on hepatic phase II phenolsulfotrnasferases and antioxidant status in vivo. According to the results, phenolic acids in dosage of 100 mg/body weight significantly increased PST-P and PST-M activities as compared with the that of the control rats (p<0.05). Reverse transcription polymerase chain reaction results indicated that the changes in PST-P and PST-M mRNA levels by phenolic acids were similar to those noted in the enzymes activity levels. The plasma obtained form phenolic acids-administrated rats were significantly increased the oxygen radical absorbance capacity (ORAC) values than that form control rats. In a bioavailability study, following oral administration of gallic acid and p-coumaric acid (100 mg/kg body weight), the phenolic acid were detected in the plasma and the Cmax values after 2.0 h administration were 665±23, and 550±33 nmol/L, respectively. There was a significant correlation between the activity of both forms of PSTs and the antioxidant capacity of ORAC value by phenolic acids, suggesting that phenolic acids might alter sulfate conjugation and antioxidant capacity in living systems. (6) Nrf2 can initiate transcription of many antioxidant response element (ARE) mediated antioxidant genes expression. In this study, it was found that antioxidant phenolic acids could induce translocation of cytoplasmic Nrf2 into nucleus and JNK/p38 MAPK signaling cascade was involved in this process. It was demonstrated that antioxidant phenolic acids could remarkably induce PST-P protein expression and this induction of PST-P by antioxidant phenolic acids could be inhibited by p38 MAPK inhibitor SB203580. Taken together, we speculate that antoxidant phenolic acids activate translocation of Nrf2 into nucleus through JNK/p38 MAPK. Nrf2 then binds to the regulatory transcription region of PST gene in the nucleus and initiates gene transcription that results in final expression of chemoprotective PST-P protein.
Our results provide better understanding of the effects of phenolic acids on human PST activities, as well as information regarding the intake of phenolic antioxidant for human health.
Keywords: Platelet, human phenolsulfotransferases, phenolic acids, antioxidant activity, Synergistic effect, Cytoprotective, Signal transduction, antioxidant responsive element
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