TY - JOUR
T1 - Human liver microsomal thiol methyltransferase
T2 - Inhibition by arylalkylamines
AU - Glauser, T. A.
AU - Saks, E.
AU - Vasova, V. M.
AU - Weinshilboum, R. M.
N1 - Funding Information:
We thank Angela Hall for her contributions to these studies and Luanne Wussow for her assistance with the preparation of this manuscript. This work was supported in part by NIH grants GM 28157 and GM 35720, both to R.M.W.
PY - 1993
Y1 - 1993
N2 - 1. Thiol methyltransferase (TMT) is a microsomal enzyme catalyzing the S-methylation of aliphatic sulphydryl drugs and xenobiotics. Studies of the functional significance of S-methylation catalysed by TMT have been hampered by lack of a potent, relatively specific, non-toxic inhibitor of the enzyme. 2. Human hepatic microsomal TMT was inhibited by the arylalkylamine 2,3-dichloro-α;methylbenzylamine (DCMB), and by a series of arylalkylamines, as well as the arylamme, aniline. 3. Inhibition kinetic studies with DCMB, benzylamine, aniline, phenylethylamine and phenylethanolamine, five compounds with a wide range of IC50 values, showed 'mixed' inhibition of TMT with respect to the methyl acceptor substrate, 2-mercaptoethanol. Kis and Kii values were, respectively, 1.1 and 0.29 μM for DCMB, 160 μM each for benzylamine, 680 and 370 μM for aniline, 1640 and 1380 μM for phenylethylamine, and 2300 and 1400 μM for phenylethanolamine. Inhibition was at least partially reversible. 4. H.p.l.c. analyses were carried out with the products of enzyme reactions performed in the presence of aniline, benzylamine, and phenylethylamine to ascertain whether these compounds inhibited TMT by acting as methyl acceptors. Results showed that they did not act as methyl acceptor substrates.
AB - 1. Thiol methyltransferase (TMT) is a microsomal enzyme catalyzing the S-methylation of aliphatic sulphydryl drugs and xenobiotics. Studies of the functional significance of S-methylation catalysed by TMT have been hampered by lack of a potent, relatively specific, non-toxic inhibitor of the enzyme. 2. Human hepatic microsomal TMT was inhibited by the arylalkylamine 2,3-dichloro-α;methylbenzylamine (DCMB), and by a series of arylalkylamines, as well as the arylamme, aniline. 3. Inhibition kinetic studies with DCMB, benzylamine, aniline, phenylethylamine and phenylethanolamine, five compounds with a wide range of IC50 values, showed 'mixed' inhibition of TMT with respect to the methyl acceptor substrate, 2-mercaptoethanol. Kis and Kii values were, respectively, 1.1 and 0.29 μM for DCMB, 160 μM each for benzylamine, 680 and 370 μM for aniline, 1640 and 1380 μM for phenylethylamine, and 2300 and 1400 μM for phenylethanolamine. Inhibition was at least partially reversible. 4. H.p.l.c. analyses were carried out with the products of enzyme reactions performed in the presence of aniline, benzylamine, and phenylethylamine to ascertain whether these compounds inhibited TMT by acting as methyl acceptors. Results showed that they did not act as methyl acceptor substrates.
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U2 - 10.3109/00498259309059403
DO - 10.3109/00498259309059403
M3 - Article
C2 - 8212739
AN - SCOPUS:0027182238
SN - 0049-8254
VL - 23
SP - 657
EP - 669
JO - Xenobiotica
JF - Xenobiotica
IS - 6
ER -