Donatelli P, Marchi G, Giuliani L, Gustafsson L L, Pacifici G M
Department of Biomedicine, University of Pisa, Medical School, Italy.
Eur J Clin Pharmacol. 1994;47(4):345-9. doi: 10.1007/BF00191166.
This study was designed to determine whether both enantiomers of chloroquine inhibit histamine N-methyltransferase. The mean estimates of IC50 for the d- and l-enantiomers of chloroquine were 4.9 and 17.8 microM (liver), respectively and 6.9 and 21.6 microM (brain), respectively. Ki estimates were significantly lower with d- than with l-chloroquine; hence, d-chloroquine interacts with the enzyme more effectively than l-chloroquine. If the adverse effects of chloroquine are due to the inhibition of histamine N-methyltransferase, therapy with the l-enantiomer might have lower toxicity. The residual activity of histamine N-methyltransferase should reflect both the degree of inhibition by chloroquine and the level of enzyme expression. The rate of histamine methylation was measured in 100 human liver samples and its range and fold of variation were 29% and threefold, respectively. Susceptibility to chloroquine should be greater in subjects with limited expression of histamine N-methyltransferase
本研究旨在确定氯喹的两种对映体是否均能抑制组胺N-甲基转移酶。氯喹d-对映体和l-对映体的IC50平均估计值在肝脏中分别为4.9和17.8微摩尔，在大脑中分别为6.9和21.6微摩尔。d-氯喹的Ki估计值显著低于l-氯喹；因此，d-氯喹与该酶的相互作用比l-氯喹更有效。如果氯喹的不良反应是由于组胺N-甲基转移酶受到抑制，那么使用l-对映体进行治疗可能毒性更低。组胺N-甲基转移酶的残余活性应既能反映氯喹的抑制程度，又能反映酶的表达水平。在100份人类肝脏样本中测量了组胺甲基化速率，其范围和变化倍数分别为29%和三倍。组胺N-甲基转移酶表达有限的受试者对氯喹的敏感性应该更高。
