The Contribution of cocoa additive to cigarette smoking addiction

RIVM report 650270002 Page 77 of 207
Histamine
of 14 C-histamine, indicating a rapid penetration of the bronchial mucosa and high
bioavailability (37). Histamine that is ingested or formed by bacteria in the
gastrointestinal tract is rapidly metabolised and excreted in the urine (13).
Distribution
Almost all mammalian tissues contain histamine in amounts ranging from less than
1µg up to more than 100 µg/g tissue. Concentrations in plasma and other body fluids
are generally very low, but human cerebrospinal fluid contains significant amounts.
The mast cell is the predominant storage site for histamine in most tissues, especially
in the skin, the mucosa of the bronchial tree and the intestinal mucosa (13).
Metabolism
Every mammalian tissue that contains histamine is able to synthesise it from histidine
by virtue of its contents of L-histidine decarboxylase. Since this enzym is inducible,
the histamine-forming capacity at non-mastcell sites is subject to regulation by
various physiological and other factors. There are two major paths of histamine
metabolism in man. The more important of these involves methylation and is
catalysed by the enzym histamine-N-methyltransferase, which is widely distributed.
Most of the product, N-methylhistamine is converted by monoamine oxidase (MAO)
to N-methyl imidazole acetic acid. Alternatively, histamine undergoes oxidative
deamination catalyzed mainly by the nonspecific enzyme diamine oxidase (DAO).
The products are imidazole acetic acid and eventually its riboside (13).
Excretion
In mammals, the metabolites resulting from catalysation are excreted in the urine
(13). 14 C-histamine was administered intrabronchially to asthmatic patients and
controls. The urinary excretion of total radioactivity, 14 C-histamine and its
radioactive metabolites was measured. It was found that the excretion of total
radioactivity was complete within 24 h. The excretion rate was equal to that observed
after intravenous injection of 14 C-histamine, indicating a rapid penetration of the
bronchial mucosa. However, the diuresis seemed to be of importance for the
excretion rate (37). The urinary excretion of histamine and its metabolites,
methylhistamine, methylimidazoleacetic acid and imidazoleacetic acid, was
measured under standardized dietary conditions in 24 women with normal
pregnancies and in eleven patients with toxaemia of pregnancy. A slight increase in
the urinary excretion of methylimidazoleacetic acid was observed in normal
pregnancy as well as in toxaemia of pregnancy compared to non-pregnant women. In
two toxaemic patients and in one of the healthy subjects the urinary excretion of
unmetabolized histamine was moderately increased. Despite the very high diamino
oxidase activity in the plasma and in the uterus during pregnancy, there were no signs
of altered catabolism of endogenous histamine in the pregnant women. Smoking
increased the urinary excretion of the quantitatively dominant histamine metabolite,
methylimidazolacetic acid (38).
Kinetic parameters
Histamine was co-administered with interleukin-2 (IL-2) in a phase III study in
patients with metastatic melanoma, offering a survival advantage over IL-2 treatment
alone. In order to characterize any drug-drug interactions between IL-2 and
histamine, a phase I pharmacokinetic (PK) study was initiated. Histamine and IL-2