Exploration of the role of phenolsulfotransferase in the disposition of serotonin in human platelets: implications for a novel therapeutic strategy against depression.
Human platelets have been used as models to evaluate a possible role for phenolsulfotransferase (PST) in the disposition of 5-hydroxytryptamine (5HT). The platelet M-type PST, which prefers biogenic amines as substrates, appears to be unique in its ability to O-sulfate dopamine and 4,6-difluoro-5HT (diF-5HT) at rates 6-20 times faster than 5HT. The assay technique employed can make a critical difference in the measured rates of sulfation of these amines, however. For example, use of purified alveolysin toxin to disrupt cell membranes can result in as much as a 20-fold increase in the observed velocity of 5HT O-sulfation. In intact platelets, only 1-3% of the total amount of radiolabelled material (as measured by a thin-layer chromatographic procedure) is the O-sulfate conjugate of 5HT. Up to 20% of the total H3-5HT taken up by cells becomes O-sulfated following treatments such as reserpine which lead to a large increase in the extra-vesicular (cytoplasmic) pool of H3-5HT. Availability of a compound producing irreversible inhibition of M-type PST activity would facilitate exploration of intra-platelet 5HT metabolism, but compounds reported to inhibit essentially 100% of the PST activity in other systems do not appear to interfere with the action of human platelet M-type PST. Because of the apparent similarity between PST present in human platelets and in nerve microsacs prepared from guinea pig brains, PST inhibitors effective in human platelets might also be valuable for studies of amine metabolism in brain tissue. Possible candidates are discussed. Furthermore, the behavioral effects of compounds proving to be PST inhibitors could provide novel therapeutic approaches to the problem of depressive illness.
D000928:Antidepressive Agents / Q000138:chemical synthesis*; D015239:Arylsulfotransferase; D001792:Blood Platelets / Q000201:enzymology*; D003866:Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D012701:Serotonin / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000378:metabolism*; D013466:Sulfurtransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000928:Antidepressive Agents; C033396:5-hydroxytryptamine O-sulfate; D012701:Serotonin; D013466:Sulfurtransferases; D015239:Arylsulfotransferase