The effect of pharmacologic inhibition of phospholipid methylation on human
platelet function
SJ Shattil, JA Montgomery and PK Chiang
Human platelets are capable of synthesizing their major membrane
phospholipid, phosphatidylcholine, by a methylation pathway. This involves
the sequential transfer of methyl groups from S-adenosyl-L- methionine
(AdoMet) to phosphatidylethanolamine, and in the process, AdoMet is
converted to S-adenosylhomocysteine (AdoHcy). The activity of this
methylation pathway is decreased upon stimulation of platelets by various
agonists. We inhibited methylation reactions pharmacologically to see
whether this inhibition plays any role in the process of platelet
activation. Two inhibitors of AdoHcy hydrolase, 3-deaza- adenosine and
3-deaza-(+/-)aristeromycin (500 microM each), were effective in increasing
platelets levels of AdoHcy and preventing turnover of AdoMet. Also, these
compounds were equipotent in inhibiting platelet phospholipid methylation.
However, while 3-deaza-adenosine potentiated platelet aggregation and
14C-serotonin release induced by epinephrine or adenosine diphosphate (ADP)
(p less than 0.01), 3-deaza- aristeromycin had no such effect. Neither
compound affected platelet responses to thrombin or collagen. Inhibition of
methylation reactions was not the only biochemical effect of
3-deaza-adenosine since it also blunted significantly the elevation of
platelet cyclic adenosine monophosphate (AMP) levels induced by
prostaglandin E1 (p less than 0.02). Therefore, these studies demonstrate
that inhibition of platelet phospholipid methylation, per se, has no
discernable effect on the function of human platelets. The methylation
pathway, though active in platelets, does not appear to be primarily
involved in membrane events responsible for platelet activation.
Volume 59,
Issue 5,
pp. 906-912,
05/01/1982
Copyright © 1982 by The American Society of Hematology
