| Pharmacogenomics of
antihistamines
Pharmacogenomics is a science to study the relationship between gene
sequence polymorphism and drug effect diversity35. Pharmacogenomics
aims at drug effect and safety, it has contributed not only to the
acknowledgment of gene polymorphism responsible for variation in drug
response but also to the new drugs or new drug delivery methods
development process 36.
In recent decades, the rapid development of pharmacogenomics has endowed
a new connotation and brought new opportunities for individualized drug
use, which makes today’s clinical individualized drug use more
far-reaching 37.
Antihistamine is a drug with a marked therapy effect that is widely used
in allergic diseases, while individual variability in drug use has been
reported. Individual differences may be mainly manifested as differences
in pharmacodynamics and adverse reactions. Antihistamine
pharmacogenomics has found that gene polymorphism plays an important
role in its application (Fig 1). The genetic variation of metabolic
enzyme, transporters, and targeted molecules influences the
distribution, metabolism, and excretion of antihistamines through
molecular mechanisms. Also, genes variation related disease like
urticaria or allergic rhinitis may affect the application of
antihistamine. A summary of the effect of drug metabolism enzyme,
transporters, and receptors polymorphism on antihistamine is listed in
Table 1. This paper summarizes the current researches of
pharmacogenomics on antihistamines, hoping to have a certain
significance for further research in this field and guiding clinical
medication in the future.
| Drug metabolism enzyme
polymorphism
The
cytochromes P450(CYPs) is the main enzyme system of drug metabolism,
which contains many subgroups. Human CYPs are mainly membrane-associated
proteins that are widely expressed in most tissues, especially in liver
tissue with specific CYPs types distributed38,
39. The gene variation of
CYPs can change its susceptibility
to induction and inhibition, then influence the pharmacokinetics of
drugs. Therefore, CYPs play an important role in inter-individual drug
response that is closely linked to the efficacy and side effects of
drugs 40. Most
antihistamines are metabolized by the liver CYP450 enzyme system.
Cytochrome P450 (CYP) 3A is an important group of the CYP450 enzyme
system, which is most abundant in the liver and gastrointestinal tract41. However, previous
studies have shown that due to the single nucleotide polymorphisms
(SNPs) in gene sequences, the enzyme encoded by the CYP3A allele has
little or no activity42. The members of the
CYP3A subfamily mainly include four genes that lie within a 231 kb
region of chromosome 7q22.1, namely CYP3A4(MIM124010),
CYP3A5(MIM605325), CYP3A7(MIM605340), and CYP3A43(MIM606534)41. Human cytochrome
P450(CYP)3A4 is involved in the metabolism of about 50% of commonly
used drugs 43,
44, among which the relationship between
genetic polymorphism of CYP450 and antihistamines has been reported.
Rupatadine (RUP) is an oral antihistamine and platelet activator
antagonist that metabolizes desloratadine and 3-Hydroxydesloratadin
primarily through CYP3A4 mediated metabolism. CYP3A5*3 can reduce
the expression of CYP3A5, and the polymorphism of the CYP3A5 gene may
significantly affect the activity pattern of CYP3A42. Yuqing Xiong et al45 found thatCYP3A5*1/*1 carrier had high metabolic activity and low
transporter activity, while CYP3A5*1 /*3 carriers had the
opposite effect, which may lead to different concentrations of
rupatadine (RUP) in the
gastrointestinal tract and blood. Differences in concentration will lead
to various treatment effectiveness and toxicity. The underlying
mechanism of CYP3A5 polymorphism in individual differences in
antihistamine application needs to be further demonstrated. Maekawa et
al found that variants of CYP3A4 such as CYP3A4*16 and CYP3A4*18 alleles
showed different catalytic activities for different CYP3A4 substrates46. In another study,
possible genetic variants of CYP3A4, such as CYP3A4*2, *7, *16, and *18,
may lead to drug-drug interaction individual-mediated variation by
CYP3A4 inhibitor cimetidine47. Therefore, when
antihistamines are used together with other drugs, the polymorphism of
CYP3A4 in patients may be taken into account and the drug should be
reasonably applied.
The CYP2 family is the largest group of the human P450 enzyme family.
The CYP2J subfamily contains a single human gene, CYP2J2, which was
originally proposed by Kikuta and his colleagues48. Human cytochrome
CYP2J2 is highly expressed in the heart and is involved in a variety of
metabolic reactions, including oxidation of important drugs and
epoxidation of endogenous arachidonic acid49,
50. It is involved in the metabolism of
a variety of antihistamine drugs, including ebastine, terfenadine, and
astemizole 51,
52. But the contribution of CYP2J2 to
overall clearance is not clear and may strongly depend on the tissue53,
54. At least 10 genetic variants of
CYP2J2 have been listed on the CYP alleles website. Jeong et al55used the
antihistamine terfenadine as a substrate to analyze the biochemical
characteristics of CYP2J2*8, *9, and *10 alleles (G312R,
P351L, and P115L) containing non-synonymous SNPs and biochemical
characteristics of P351L and P115L. It was found that the metabolic
activity of the two mutant enzymes P351L and P115L was similar to that
of the wild type, and the changes of G312R amino acids affect the
structural stability of the P450 heme environment. This may affect the
metabolism of antihistamines like terfenadine and cause corresponding
adverse reactions, but the specific mechanism of influence and the
manifestation of adverse reactions are not described in the paper.
CYP2D6 is highly correlated with drug metabolism. CYP2D6 is involved in
the metabolism of about 25% of clinically used drugs, and its gene
polymorphism changes the pharmacokinetics of those with poor or
extensive metabolism 56,
57. CYP2D6 is encoded by a highly
polymorphic gene 58.
Based on the activity of CYP2D6 isozymes, it identifies four types of
carriers with different gene polymorphisms: normal (extensive), poor,
intermediate, and hypertrophic metabolites59. Extensive
metabolite (EM): The main alleles were *1 and *2 ; Poor
metabolite (PM): The main allele was *3~*6 ;
Intermediate metabolite (IM): The primary alleles were *10 and*41 . Wild-type allelic hypervelocity metabolites included
individuals with gene variants (CYP2D6*1)xN and(CYP2D6*2)xN duplication and multiplication60. The most common
allelic variants associated with the poor phenotype of metabolites wereCYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*660. People with poor
metabolism are more likely to be affected by poor substrate metabolism.
CYP2D6 is the main metabolic pathway for many sedative drugs in the
central nervous system56,
61. Antihistamine effects are also known
to occur with antidepressants and antipsychotic drugs62, such as
mirtazapine, esmirtazapine, mianserin, and meclizine. Mirtazapine and
mianserin have an H1 antagonist effect obviously, studies have shown
that people with dysmetabolic CYP2D6 phenotypes are more sensitive to
the potential damage of esmirtazapine and are more likely to be exposed
to high levels of drugs or metabolites63. Besides CYP2D6,
another study has found that mirtazapine metabolism may also be
influenced differently by the CYP3A5 genotype and by multiple
combinations (three or more)64, so there may also
be a greater chance of adverse reactions. Meclizine has long been a
widely accepted antihistamine used in the preventative treatment and
management of nausea, vomiting, and dizziness associated with exercise
disorders 65. Zhijun
Wang et al 65found that
CYP2D6 was the dominant enzyme in
meclizine metabolism, and its
polymorphism might be related to the elimination of variation of
meclizine.
| Polymorphism of drug
transporters
Drug transporters are integral membrane proteins localized to tissue and
cellular membrane domains in the human body, mediating the transport of
drug molecules through active and passive mechanisms66. Influx and efflux
transporters play an important role in the absorption, tissue
distribution, and excretion of drugs67.
It
has been reported that non-sedating antihistamines are characterized by
the efflux function of P-glycoprotein(P-gp) through the blood-brain
barrier 68.
P-glycoprotein is an ATP-dependent carrier protein first discovered in
tumor cells and expressed by multi-drug resistance genes69. It exists in a
variety of tissues in the human body, such as the liver, kidney, brain,
and so on 69-73. P-gp
is encoded by the MDR1(ABCB1) gene74. P-gp gene
polymorphism, including 1236C>T,
2677G>A/T, and 3435C>T mutation
produced, and conflicting results have been obtained in the study of the
pharmacokinetics of fexofenadine. Persons with 2677AA/3435CCgenotype of MDR1(ABCB1) have lower plasma concentrations of fexofenadine
after a single oral taking compared to the person with other genotypes75. On the contrary,
Drescher et al found that there was no significant correlation ofC3435T polymorphism with the H1 receptor occupancy by the
P-glycoprotein substrate fexofenadine76. In addition to
P-gp, organic anion transport polypeptide (OATPs) that encoded by the
SLCO gene 77 and
multidrug resistance protein 2(MRP2) that encoded by the ABCC2genes 78 may also work
on fexofenadine pharmacokinetics. OATP1B1, 1B3, and 2B1 involved in
fexofenadine liver metabolism in OATP drug transporters79-81 and Akamine et al82studied the effect of
drug transporter polymorphism on the pharmacokinetics of fexofenadine
and found that the pharmacokinetics of S-fexofenadine was related to the
single polymorphism of SLCO2B1 and multiple polymorphism
combinations of ABCB1 C1236T, C3435T, and ABCC2 C-24T. In
the small intestine and liver, the binding of multiple transporters
involved in OATP, P-GP, and multidrug resistance protein 2(MRP2) may
strongly respond to exposure to fexofenadine, resulting in different
configurations between enantiomers. In another study, the relationship
between SLCO2B1 , the encoding gene of OATP transporter, and the
antihistamine drug fexofenadine was also pointed out. Through in vitro
kinetics studies, this study showed that SLCO2B1
c.[1457C>T]2 allele reduce OATP2B1 transport function
and the bioavailability of fexofenadine83, which may affect
the efficacy and toxicity of the drug.
| Receptor
polymorphism
As a drug target for antihistamines, the change of the histamine
receptor, especially the polymorphism of the receptor gene, will also
affect the effect of drugs and lead to the individual difference.
Therefore, the study of the variation of the receptor gene is of great
significance. Gu et al84found that among HRH4
genes, rs77485247 mutant (TA+AA) and rs77041280 mutant (TA+TT) may
reduce the efficacy of H1A orally, which may increase the incidence of
adverse reactions. The polymorphism of HRH4 rs77485247 and rs77041280
may affect the therapeutic effect of antihistamines. A study on
histamine H1 receptor gene polymorphism and efficacy in Chinese Han
patients with allergic rhinitis showed that the efficacy of H1
antihistamines was enhanced in AR patients with HRH1 wild-type gene
type, while the heterozygous mutant (CT) and homozygous mutant (TT)
genes have a higher risk of AR and may affect the efficacy of
antihistamines and increase their adverse reactions85.
| Disease susceptibility
and drug efficacy, side
effects
Antihistamines are the first-line therapeutic drugs for urticaria, which
is an allergic disease mainly involved with mast cells. The
polymorphisms of the genes involved in the development and progression
of urticaria may also affect the efficacy and toxicity of
antihistamines. In recent years, the research in this field has been
increasing and relevant research reports have provided us with some
ideas. Reports in this area include FCER1A, CACNA1C, ORAI1,
C5AR1, and CRTH2, as shown in Table 2. FCER1A is an
important immune-related gene that encodes ligand-binding subunit a
chain (FceRIɑ) of high-affinity IgE receptor (FcɛRI) to trigger
IgE-mediated allergic reactions, related to the total level of IgE serum86-88. High total serum
IgE levels are closely correlated with the clinical expression and
severity of allergic diseases89-91. However, no
association between FCER1A and allergic rhinitis was found in one
study 92. For
urticaria, Guo et al of our group have found that among the rs2298805,
rs10908703, and rs2494262 genotypes of FCER1A , rs2298805
polymorphism is associated with the risk of CSU and serum total IgE
concentration, and CSU patients with rs2298805A allele show a better
response to non-sedate H1-antihistamine93. Further functional
studies are needed to elucidate the mechanism of rs2298805 affecting the
pathogenesis of urticaria and the therapeutic effect of non-sedated
H1-antihistamine.CACNA1C codes for the pore-forming α1C subunit of the L-type
voltage-gated calcium channel (LTCC). Our group’s study on genetic
polymorphism of the CACNA1C gene and susceptibility and prognosis
of chronic spontaneous urticaria showing that genetic polymorphisms of
the CACNA1C gene can affect the mast cell activation and
degranulation process, thus affecting the onset of the CSU94. A/G mutation at
rs58619945 in patients may be related to the onset of chronic
spontaneous urticaria, different alleles at rs216008 may be related to
the efficacy of desloratadine, and mutations at rs7316246 may indicate
differences in the severity and prognosis of the disease94. The degranulation
process of mast cells is mainly mediated by Ca2+influx mediated by calcium channels activated by calcium releasing
enzymes. ORAI1 is a plasma
membrane protein, encoded by the ORAI1 gene, and
calcium-release-activated calcium (CRAC) channels pore formation subunit95. Studies on ORAI1
knockout mice have shown that ORAI1 plays an important role in mast cell
degranulation, leukotriene (LTC4) secretion, histamine release, and
TNF-ɑ secretion 96,
97. Our group reported98 that
rs3741595, rs3741596, rs12320939, and
rs12313273, especially the rs3741596A allele, were significantly
increased in CSU patients and rs12320939T allele was associated with
increased expression of the ORAI1 gene. The ORAI1 gene
allele rs3741596A enhanced the degranulation activity of mast cells and
the rs3741595C may be associated with the therapeutic effects of
desloratadine. C5a receptor (C5aR) plays an important role in mast cell
activation and degranulation by regulating the complement C5a pathway,
thus enhancing the release of histamine. C5a/C5aR pathway promotes
histamine release and leads to CSU inflammatory response, human C5aR is
encoded by C5AR1 (also known as C5aR) gene, and Yan et al99 in our group founded
that C5AR1 SNP -1330T/G can be used as an effective
pharmacodynamics predictor of the efficacy of non-sedating
H1-antihistamine drugs in CSU patient. The chemoattractant
receptor-homologous molecule expressed on Th2 Lymphocytes (CRTH2) is a
member of the G protein-coupled, seven-transmembrane receptor family and
it has been reported to be associated with mast cell-related allergic
diseases 100,
101. Palikhe NS et al102 founded that CRTH2
gene polymorphism(-466T>C and-129C>A ) may not be associated with susceptibility
in Korean patients with chronic urticaria, but the CRTH2-466T>C gene polymorphism was associated with the
required antihistamine dose and CU patients with the CRTH2 -466Tgenotype need a higher dose.
There have been a few clear reports on gene polymorphism and the exact
adverse effects of antihistamines. Sedating side effects is a major
adverse effect of first-generation and some second-generation
antihistamines. Juan et al in our team103 evaluated the
association between HRH1 gene rs901865 polymorphism and sedating side
effects severity in 114 Chinese CSU patients treated with desloratadine.
HRH1 rs901865 G/G polymorphism was found to be associated with an
increase in desloratadine induced lethargy but did not affect drug
efficacy or increase the risk of CSU. This study will be important for
predicting the severity of narcolepsy adverse reactions after the
desloratadine application. Cardiotoxicity is a serious adverse reaction
induced by antihistamines. Among second-generation antihistamines,
terfenadine and astemizole have been reported to cause tip torsion
ventricular tachycardia with prolonged QT interval and even death due to
drug overdose and drug interactions104-107.
Antihistamines can cause cardiotoxicity by blocking the current of a
human Etherago-go-related gene (HERG). A614v-HERG mutations have been
shown to cause syncope in patients with a first-generation H1 receptor
antagonist and hydroxyzine can inhibit the channel current of the gene108. The correlation
between gene polymorphism and adverse cardiotoxicity induced by
antihistamines is scarce, more research needs to be done in the future.