DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 32–1
Characteristics of Histamine Receptors
H 1
H 2
∗
H 3
H 4
Size (amino acids) 487 359 329-445 390
G protein coupling G q/11
G s
G i/o
G i/o
(second messengers) (a Ca 2+ ; a NO (a cAMP) (b cAMP; (b cAMP; a Ca 2+ )
and a cGMP)
a MAP kinase)
Distribution Smooth muscle, Gastric parietal CNS: presynaptic Cells of hematopoietic
endothelial cells, cells, cardiac origin
CNS
muscle, mast
cells, CNS
Representative agonist 2-CH 3
-histamine Amthamine (R)-α-CH 3
-histamine 4-CH 3
-histamine
Representative Chlorpheniramine Ranitidine Tiprolisant JNJ7777120
antagonist
cAMP, cyclic AMP; cGMP, cyclic GMP; CNS, central nervous system; NO, nitric oxide.
*At least 20 alternately spliced H 3
isoforms have been detected at the mRNA level. Eight of these isoforms, ranging in size from 329-445 residues,
were found to be functionally competent by binding or signaling assays (see Esbenshade et al., 2008)
histamine in secretory granules is slow, and when tissues rich in
mast cells are depleted of their histamine stores, it may take weeks
before concentrations return to normal levels. Non–mast cell sites
of histamine formation include the epidermis, the gastric mucosa,
neurons within the CNS, and cells in regenerating or rapidly growing
tissues. Turnover is rapid at these non–mast cell sites because
the histamine is released continuously rather than stored. Non–mast
cell sites of histamine production contribute significantly to the
daily excretion of histamine metabolites in the urine. Because
L-histidine decarboxylase is an inducible enzyme, the histamineforming
capacity at such sites is subject to regulation. Histamine
that is ingested or formed by bacteria in the gastrointestinal (GI)
tract does not contribute to the body’s stores; rather, it is rapidly
metabolized, and the metabolites are eliminated in the urine.
There are two major paths of histamine metabolism in
humans (Figure 32–2). The more important is ring methylation to
form N-methylhistamine, catalyzed by histamine-N-methyltransferase,
which is distributed widely. Most of the N-methylhistamine
formed is then converted to N-methylimidazole acetic acid by
monoamine oxidase (MAO), and this reaction can be blocked by
MAO inhibitors (Chapters 8, 15, and 22). Alternatively, histamine
may undergo oxidative deamination catalyzed mainly by the nonspecific
enzyme diamine oxidase, yielding imidazole acetic acid,
which is then converted to imidazole acetic acid riboside. These
metabolites have little or no activity and are excreted in the urine.
Measurement of N-methylhistamine in urine affords a more reliable
index of histamine production than assessment of histamine
itself. Artifactually elevated levels of histamine in urine arise from
genitourinary tract bacteria that can decarboxylate histidine. In
addition, the metabolism of histamine appears to be altered in
patients with mastocytosis such that determination of histamine
metabolites is a more sensitive diagnostic indicator of the disease
than histamine.
H 3 CN
N-Methyltransferase
N
L-Histidine
decarboxylase
CH 2 CH 2 NH 2
N-METHYLHISTAMINE
MAO-B
H 3 CN
N
CH 2 COOH
N-METHYLIMIDAZOLE
ACETIC ACID
HN
HN
N
HISTIDINE
N
HISTAMINE
COOH
CH 2 CH 2 NH 2
CH 2 CH 2 NH 2
Diamine Oxidase
IMIDAZOLEACETIC ACID
Ribose
HN
Ribose—N
N
Phosphoribosyl
transferase
N
CH 2 COOH
CH 2 COOH
IMIDAZOLEACETIC ACID
RIBOSIDE
Figure 32–2. Pathways of histamine synthesis and metabolism
in humans. Histamine is synthesized from histidine by decarboxylation.
Histamine is metabolized via two pathways, predominantly
by methylation of the ring followed by oxidative
deamination (left side of figure), and secondarily by oxidative
deamination and then conjugation with ribose.