Stereoselective inhibition by chloroquine of histamine N-methyltransferase in the human liver and brain

Abstract

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

Chloroquine-induced venodilation in human hand veins*

“…22 Evidence suggests that some of the adverse effects of chloroquine are mediated through accumulation of histamine in the tissues because chloroquine inhibits histamine-N-methyltransferase, quantitatively the most important pathway in the metabolism of histamine. 23 To test the hypothesis that local release of histamine could mediate the vasodilatory response observed, we coinfused chloroquine with HI-and H,antagonists. There was a reduction in the venodilatory response to chloroquine infusion, suggesting a role for histamine release in chloroquine-mediated venodilation.…”

Aplicação da microextração em fase liquida na análise de alguns fármacos antimaláricos e respectivos metabólitos em plasma

“…(FU et al, 1986). Donatelli et al (1994) . Em coelhos, (-)-(R)-CQ apresentou maior meia-vida de eliminação juntamente com maior área sob a curva (AUC) de (+)-(S)-DCQ (AUGUSTIJNS; VERBEKE, 1992).…”