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Lidocaine inhibits choline uptake and phosphatidylcholine biosynthesis in human leukemic monocyte‐like U937 cells
Author(s) -
Chu Arthur J.,
Lee Jack M.
Publication year - 1994
Publication title -
cell biochemistry and function
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.933
H-Index - 61
eISSN - 1099-0844
pISSN - 0263-6484
DOI - 10.1002/cbf.290120203
Subject(s) - choline , lidocaine , phosphatidylcholine , incubation , chemistry , phosphocholine , metabolism , incubation period , intracellular , biochemistry , endocrinology , pharmacology , medicine , biology , phospholipid , anesthesia , membrane
The effect of lidocaine on [ 3 H]choline uptake and the incorporation of label into phosphatidylcholine (PC) in human monocyte‐like U937 cells was investigated. Lidocaine inhibited the rate of choline uptake in a dose‐dependent manner; at 3·2 m M it resulted in a drastic reduction, by as much as 65 per cent ( n = 10; p < 0·0005) or 55 per cent ( n = 10; p < 0·0006) in a 3‐ or 6‐h incubation, respectively. Lidocaine also decreased the rate of choline incorporation into PC in a dose‐dependent manner. At the highest dose, nearly 70 per cent or 45 per cent reduction was seen in a 3‐ or 6‐h incubation, respectively. Analysis of choline‐containing metabolites showed that the major label association with phosphocholine and PC was reduced to a similar extent which was also parallel to the inhibition of choline uptake. At 3·2 m M lidocaine, the reduction of choline uptake was shown to follow a competitive inhibition. In the case of [ 3 H] choline incorporation into PC, the inhibitory pattern was shown to be of a mixed type. The pulse‐chase study dissecting the effect on choline metabolism from that on total choline uptake indicated that lidocaine exerted an additionally inhibitory effect on intracellular choline metabolism into PC. In a separate protocol in which the labelled cells were first allowed to be chased until 3 H‐incorporation into PC reached a steady state, lidocaine no longer showed any effect. These results seem to exclude the possibility of enhanced PC breakdown and further suggest that the main inhibitory effect is on the CDP‐choline pathway for PC biosynthesis. After a 3‐h treatment, CTP: cholinephosphate cytidylyltransferase (CYT) in both the cytosolic and microsomal fractions was inhibited by approximately 20 per cent, while choline kinase (CK) and choline phosphotransferase (CPT) remain relatively unchanged. There was no evidence for translocation of CYT between cytosol and microsomes. Taken together, we have demonstrated a dual inhibitory function of lidocaine which inhibits PC biosynthesis in addition to its ability to block choline uptake profoundly in U937 cells.