Interindividual variability of histamine N-methyltransferase in the human liver and kidney.

1. The aim was to investigate the possibility of interindividual variability of histamine N-methyltransferase (HNMT) in the human liver and renal cortex. The activity of HNMT was measured in 99 specimens of the human liver and in 75 specimens of the renal cortex. 2. In the liver the activity of HNMT was positively skewed. It ranged 2.9-fold with a median of 1.72 pmol/min/mg. In the renal cortex the activity of HNMT was normally distributed and ranged 2.6-fold with a mean and coefficient of variation of 1.35 pmol/min/mg and 21%, respectively. 3. The activities of catechol methyltransferase and thiopurine methyltransferase were measured in the renal cortex and any correlations with HNMT activity were assessed. There was a weak but significant correlation (r = 0.294, p = 0.010) between HNMT and catechol methyltransferase activities whereas HNMT activity was not correlated with thiopurine methyltransferase activity. 4. These results are consistent with the view that HNMT is well expressed in the human liver and renal cortex and that it varies among subjects.

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

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

Histamine N-methyl transferase: inhibition by drugs.

1. Histamine N-methyl transferase activity was measured in samples of human liver, brain, kidney, lung and intestinal mucosa. The mean (+/- s.d.) rate (nmol min-1 mg-1 protein) of histamine N-methylation was 1.78 +/- 0.59 (liver, n = 60), 1.15 +/- 0.38 (renal cortex, n = 8), 0.79 +/- 0.14 (renal medulla, n = 8), 0.35 +/- 0.08 (lung, n = 20), 0.47 +/- 0.18 (human intestine, n = 30) and 0.29 +/- 0.14 (brain, n = 13). 2. Inhibition of histamine N-methyl transferase by 15 drugs was investigated in human liver. The IC50 for the various drugs ranged over three orders of magnitude; chloroquine was the most potent inhibitor. 3. The average IC50 values for chloroquine were 12.6, 22.0, 19.0, 21.6 microM in liver, renal cortex, brain and colon, respectively. These values are lower than the Michaelis-Menten constant for histamine N-methyltransferase in liver (43.8 microM) and kidney (45.5 microM). Chloroquine carried a mixed non-competitive inhibition of hepatic histamine N-methyl transferase. Some side-effects of chloroquine may be explained by inhibition of histamine N-methyl transferase.