Elucidating the potential of chlorogenic acid for controlling Morganella psychrotolerans growth and histamine formation.

AIM: To investigate the inhibitory impact of chlorogenic acid (CGA) on the growth of Morganella psychrotolerans and its ability to form histamine. METHODS AND RESULTS: The antimicrobial effect of CGA on M. psychrotolerans was evaluated using the minimum inhibitory concentration (MIC) method, revealing an MIC value of 10 mg ml-1. The alkaline phosphatase (AKP) activity, cell membrane potential, and scanning electron microscopy images revealed that CGA treatment disrupted cell structure and cell membrane. Moreover, CGA treatment led to a dose-dependent decrease in crude histidine decarboxylase (HDC) activity and gene expression of histidine decarboxylase (hdc). Molecular docking analysis demonstrated that CGA interacted with HDC through hydrogen bonds. Furthermore, in situ investigation confirmed the efficacy of CGA in controlling the growth of M. psychrotolerans and significantly reducing histamine formation in raw tuna. CONCLUSION: CGA had good activity in controlling the growth of M. psychrotolerans and histamine formation.

Whole-brain mapping of histaminergic projections in mouse brain.

Histamine is a conserved neuromodulator in mammalian brains and critically involved in many physiological functions. Understanding the precise structure of the histaminergic network is the cornerstone in elucidating its function. Herein, using histidine decarboxylase (HDC)-CreERT2 mice and genetic labeling strategies, we reconstructed a whole-brain three dimensional (3D) structure of histaminergic neurons and their outputs at 0.32 × 0.32 × 2 µm3 pixel resolution with a cutting-edge fluorescence microoptical sectioning tomography system. We quantified the fluorescence density of all brain areas and found that histaminergic fiber density varied significantly among brain regions. The density of histaminergic fiber was positively correlated with the amount of histamine release induced by optogenetic stimulation or physiological aversive stimulation. Lastly, we reconstructed a fine morphological structure of 60 histaminergic neurons via sparse labeling and uncovered the largely heterogeneous projection pattern of individual histaminergic neurons. Collectively, this study reveals an unprecedented whole-brain quantitative analysis of histaminergic projections at the mesoscopic level, providing a foundation for future functional histaminergic study.

Disruption of histamine/H1R-STAT3-SLC7A11 axis exacerbates doxorubicin-induced cardiac ferroptosis.

Doxorubicin (DOX) is widely used in the treatment of various cancers, increasing the great risk of adverse cardiovascular events, while the clinical intervention effect is not ideal. Histamine has been documented to participate in pathophysiological processes of cardiovascular diseases and inflammation-associated carcinogenesis. However, the potential roles of histamine in antitumor-related cardiotoxicity have not been fully elucidated. In this study, cardiomyocytes (hiPSC-CMs, HL-1 cells) and mice were treated with DOX to establish DOX-induced cardiotoxicity (DIC) models. Histidine decarboxylase knockout mice (HDC-/-) mice and histamine 1 receptor (H1R) antagonist were used to explore the effect of histamine/H1R signaling on DIC. Our results demonstrated that histamine deficiency or pharmaceutical inhibition of H1R accelerated myocardial ferroptosis, which is responsible for the aggravated DIC both in vivo and in vitro, while the supplementation of exogenous histamine reversed these changes. Our data revealed that the dysfunction of histamine/H1R signaling repressed the activation of transducer and activator of transcription 3 (STAT3), accompanying with decreased expression of solute carrier family7member11 (SLC7A11), a major modulator of ferroptosis. Conclusively, the disruption of histamine/H1R axis triggered ferroptosis and exacerbated DIC possibly by modulating STAT3-SLC7A11 pathway. Our findings point to a potential therapeutic target for DIC and provide more consideration on the usage of antihistamine drugs.

Identification of essential element determining fruit-specific transcriptional activity in the tomato HISTIDINE DECARBOXYLASE A gene promoter.

KEY MESSAGE: In SlHDC-A promoter, SlHDC-A core-ES is an essential region for fruit-specific expression and interacts with GATA, HSF and AP1. Triplication of essential region was proposed as a minimal fruit-specific promoter. In plant biotechnology, fruit-specific promoter is an important tool for the improvement and utilization of tomato fruit. To expand our understanding on fruit-specific expression, it is necessary to determine the promoter region involved in fruit-specific transcriptional activity and transcriptional regulations of the promoter. In previous study, we isolated a fruit-specific SlHDC-A core promoter specifically expressed during tomato ripening stages. In this study, we identified SlHDC-A promoter region (SlHDC-A core-ES) that is essential for fruit-specific expression of the SlHDC-A. To understand the molecular mechanisms of fruit-specific expression of the SlHDC-A promoter, we first identified the putative transcription factor binding elements in the SlHDC-A core promoter region and corresponding putative transcription factors which are highly expressed during fruit maturation. Yeast one hybrid analysis confirmed that GATA, HSF, and AP1 interact with the SlHDC-A core-ES promoter region. Further transactivation analysis revealed that expression of the three transcription factors significantly activated expression of a reporter gene driven by SlHDC-A core-ES promoter. These results suggest that GATA, HSF, and AP1 are involved in the fruit-specific expression of SlHDC-A promoter. Furthermore, the synthetic promoter composed of three tandem repeats of SlHDC-A core-ES showed relatively higher activity than the constitutive 35S promoter in the transgenic tomato fruits at the orange stage. Taken together, we propose a new synthetic promoter that is specifically expressed during fruit ripening stage.

Antagonism of histamine H3 receptor promotes angiogenesis following focal cerebral ischemia.

Our previous study showed that H3 receptor antagonists reduced neuronal apoptosis and cerebral infarction in the acute stage after cerebral ischemia, but through an action independent of activation of histaminergic neurons. Because enhanced angiogenesis facilitates neurogenesis and neurological recovery after ischemic stroke, we herein investigated whether antagonism of H3R promoted angiogenesis after brain ischemia. Photothrombotic stroke was induced in mice. We showed that administration of H3R antagonist thioperamide (THIO, 10 mg·kg-1·d-1, i.p., from D1 after cerebral ischemia) significantly improved angiogenesis assessed on D14, and attenuated neurological defects on D28 after cerebral ischemia. Compared with wild-type mice, Hrh3-/- mice displayed more blood vessels in the ischemic boundary zone on D14, and THIO administration did not promote angiogenesis in these knockout mice. THIO-promoted angiogenesis in mice was reversed by i.c.v. injection of H3R agonist immepip, but not by H1 and H2 receptor antagonists, histidine decarboxylase inhibitor α-fluoromethylhistidine, or histidine decarboxylase gene knockout (HDC-/-), suggesting that THIO-promoted angiogenesis was independent of activation of histaminergic neurons. In vascular endothelial cells (bEnd.3), THIO (10-9-10-7 M) dose-dependently facilitated cell migration and tube formation after oxygen glucose deprivation (OGD), and H3R knockdown caused similar effects. We further revealed that H3R antagonism reduced the interaction between H3R and Annexin A2, while knockdown of Annexin A2 abrogated THIO-promoted angiogenesis in bEnd.3 cells after OGD. Annexin A2-overexpressing mice displayed more blood vessels in the ischemic boundary zone, which was reversed by i.c.v. injection of immepip. In conclusion, this study demonstrates that H3R antagonism promotes angiogenesis after cerebral ischemia, which is independent of activation of histaminergic neurons, but related to the H3R on vascular endothelial cells and its interaction with Annexin A2. Thus, H3R antagonists might be promising drug candidates to improve angiogenesis and neurological recovery after ischemic stroke.

Relationship of histamine expression with chemokine balance in the tumor microenvironment of squamous cell carcinoma of the tongue.

BACKGROUND: Tumor-associated macrophages in the tumor microenvironment (TME), as a factor affecting lymphocytes, have received much attention. Both lymphocytes and macrophages can switch the expression of histamine receptors. In this study, we investigated the role of histamine in the TME of tongue squamous cell carcinoma (SCC). METHODS: Sixty-seven patients with stage I tongue SCC were studied. Histamine was evaluated by the expression of L-histidine decarboxylase (HDC). Macrophages, T lymphocytes, and lymph vessel density, as well as the Ki-67 labeling index (LI) and depth of invasion (DOI), were compared with HDC expression. RESULTS: HDC expression was significantly affected by the TME. The DOI, worst pattern of invasion, and Ki-67 LI were associated with histamine expression. C-C motif chemokine ligand (CCL) 2 and CCL22 were co-expressed with histamine H1 and H2 receptors. Histamine expression was most affected by the DOI. CONCLUSIONS: Tongue SCC expressing histamine affected the TME via histamine receptors and chemokines.

Tadr is an axonal histidine transporter required for visual neurotransmission in Drosophila.

Neurotransmitters are generated by de novo synthesis and are essential for sustained, high-frequency synaptic transmission. Histamine, a monoamine neurotransmitter, is synthesized through decarboxylation of histidine by histidine decarboxylase (Hdc). However, little is known about how histidine is presented to Hdc as a precursor. Here, we identified a specific histidine transporter, TADR (torn and diminished rhabdomeres), which is required for visual transmission in Drosophila. Both TADR and Hdc localized to neuronal terminals, and mutations in tadr reduced levels of histamine, thus disrupting visual synaptic transmission and phototaxis behavior. These results demonstrate that a specific amino acid transporter provides precursors for monoamine neurotransmitters, providing the first genetic evidence that a histidine amino acid transporter plays a critical role in synaptic transmission. These results suggest that TADR-dependent local de novo synthesis of histamine is required for synaptic transmission.

Histamine Deficiency Promotes Myofibroblasts Transformation from HDC-Expressing CD11b+ Myeloid Cells in Injured Hearts Post Myocardial Infarction.

Myocardial infarction (MI) is a significant contributor to the development of heart failure. Histidine decarboxylase (HDC), the unique enzyme that converts L-histidine to histamine, is highly expressed in CD11b+ immature myeloid cells. However, the relationship between HDC-expressing macrophages and cardiac myofibroblasts remains to be explained. Here, we demonstrate that the GFP (green fluorescent protein)-labeled HDC+CD11b+ myeloid precursors and their descendants could differentiate into fibroblast-like cells in myocardial interstitium. Furthermore, we prove that CD11b+Ly6C+ monocytes/macrophages, but not CD11b+Ly6G+ granulocytes, are identified as the main cellular source for bone marrow-derived myofibroblast transformation, which could be regulated via histamine H1 and H2 receptor-dependent signaling pathways. Using HDC knockout mice, we find that histamine deficiency promotes myofibroblast transformation from Ly6C+ macrophages and cardiac fibrosis partly through upregulating the expression of Krüppel-like factor 5 (KLF5). Taken together, our data uncover a central role of HDC in regulating bone marrow-derived macrophage-to-myofibroblast transformation but also identify a histamine receptor (HR)-KLF5 related signaling pathway that mediates myocardial fibrosis post-MI. CD11b+Ly6C+ monocytes/macrophages are the main cellular source for bone marrow-derived myofibroblast transformation. Histamine inhibits myofibroblasts transformation via H1R and H2R-dependent signaling pathways, and ameliorates cardiac fibrosis partly through upregulating KLF5 expression.

The Histamine System in Zebrafish Brain: Organization, Receptors, and Behavioral Roles.

Three of the four histamine receptors have been identified in zebrafish. Whereas only one histamine receptor 1 gene (hrh1) is known, two copies of histamine receptor 2 (hrh2a and hrh2b) have been identified. Although initially only one gene encoding for histamine receptor 3 (hrh3) was recognized in zebrafish, the genome database contains information for two more hrh3-like genes, whereas no genes corresponding for histamine receptor 4 with expression mainly in the immune system have been identified. Hrh1 and hrh3 show prominent uneven expression in the zebrafish brain, with the strongest expression in the dorsal telencephalon. Quantitatively significant expression of hrh1, hrh2, and hrh3 can also be found in several peripheral organs. Whereas antagonists of hrh1, hrh2, and hrh3 all affect the locomotor activity of zebrafish larvae, interpretation of the data is hampered by a lack of information on receptor binding and signaling characteristics. Zebrafish mutants lacking any of the three histamine receptors have shown modest behavioral phenotypes, possibly due to genetic compensation. None of the receptor mutant fish have shown significant sleep phenotypes. Adult zebrafish lacking hrh3 display decreased locomotor activity. The zebrafish histamine system shows significant life-long plasticity: presenilin 1 mutant zebrafish develop an abnormally large number of histamine neurons and increased thigmotaxis and anxiety-related phenotype. Overexpression of histidine decarboxylase (hdc) in larval zebrafish is associated with an increased number of hypocretin neurons, whereas translation inhibition of hdc or exposure to α-fluoromethylhistidine leads to decreased numbers of hypocretin neurons. Current pharmacological evidence suggests that this may be mediated by hrh1. Further studies using acute, e.g., pharmacogenetic or optogenetic manipulation of selected components of brain circuits, are required to understand the full range of physiological functions of zebrafish histamine receptors.

Analysis of Immune Associated Co-Expression Networks Reveals Immune-Related Long Non-Coding RNAs during MI in the Presence and Absence of HDC.

Myocardial infarction (MI) is one of the most common cardiovascular diseases. Although previous studies have shown that histidine decarboxylase (HDC), a histamine-synthesizing enzyme, is involved in the stress response and heart remodeling after MI, the mechanism underlying it remains unclear. In this study, using Hdc-deficient mice (Hdc-/- mice), we established an acute myocardial infarction mouse model to explore the potential roles of Hdc/histamine in cardiac immune responses. Comprehensive analysis was performed on the transcriptomes of infarcted hearts. Differentially expressed gene (DEG) analysis identified 2126 DEGs in Hdc-deficient groups and 1013 in histamine-treated groups. Immune related pathways were enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then we used the ssGSEA algorithm to evaluate 22 kinds of infiltrated immunocytes, which indicated that myeloid cells and T memory/follicular helper cells were tightly regulated by Hdc/histamine post MI. The relationships of lncRNAs and the Gene Ontology (GO) functions of protein-coding RNAs and immunocytes were dissected in networks to unveil immune-associated lncRNAs and their roles in immune modulation after MI. Finally, we screened out and verified four lncRNAs, which were closely implicated in tuning the immune responses after MI, including ENSMUST00000191157, ENSMUST00000180693 (PTPRE-AS1), and ENSMUST-00000182785. Our study highlighted the HDC-regulated myeloid cells as a driving force contributing to the government of transmission from innate immunocytes to adaptive immunocytes in the progression of the injury response after MI. We identified the potential role of the Hdc/histamine-lncRNAs network in regulating cardiac immune responses, which may provide novel promising therapeutic targets for further promoting the treatment of ischemic heart disease.

Conditional Deletions of Hdc Confirm Roles of Histamine in Anaphylaxis and Circadian Activity but Not in Autoimmune Encephalomyelitis.

Histamine is best known for its role in allergies, but it could also be involved in autoimmune diseases such as multiple sclerosis. However, studies using experimental autoimmune encephalomyelitis (EAE), the most widely used animal model for multiple sclerosis, have reported conflicting observations and suggest the implication of a nonclassical source of histamine. In this study, we demonstrate that neutrophils are the main producers of histamine in the spinal cord of EAE mice. To assess the role of histamine by taking into account its different cellular sources, we used CRISPR-Cas9 to generate conditional knockout mice for the histamine-synthesizing enzyme histidine decarboxylase. We found that ubiquitous and cell-specific deletions do not affect the course of EAE. However, neutrophil-specific deletion attenuates hypothermia caused by IgE-mediated anaphylaxis, whereas neuron-specific deletion reduces circadian activity. In summary, this study refutes the role of histamine in EAE, unveils a role for neutrophil-derived histamine in IgE-mediated anaphylaxis, and establishes a new mouse model to re-explore the inflammatory and neurologic roles of histamine.

Expression of histidine decarboxylase in melanocytes of the human skin.

Histamine-producing cells include storage-type cells (e.g., mast cells and basophils), which store histamine intracellularly, and inducible-type cells (e.g., keratinocytes and macrophages), which induce histidine decarboxylase (HDC, a key enzyme for histamine biosynthesis) activity but do not have a storage pool of histamine. Most of the studies focused on identifying HDC-expressing cells by using cultured cells, and few on investigating the localization of HDC by using skin tissues. Hence, this study conducted immunohistochemical studies using human healthy skin samples. HDC-positive and cytokeratin 14 (a marker of basal keratinocytes)-negative cells were present around the basal layer of the epidermis. These cells did not immunohistochemically react with mast cell tryptase but expressed tyrosinase (a key enzyme for melanin biosynthesis) and microphthalmia-associated transcription factor (MITF, a transcription factor controlling the expression of tyrosinase genes). Melanin granules were clearly observed around HDC-positive and MITF-positive cells. Moreover, HDC mRNA and protein were both detected in cultured normal human epidermal melanocytes. In conclusion, HDC-positive and cytokeratin 14-negative cells around the basal layer of the epidermis are melanocytes.

Changes in histidine decarboxylase expression influence extramedullary hematopoiesis in postnatal mice.

Histidine decarboxylase (HDC), histamine synthase, is expressed in hematopoietic stem cells and in lineage-committed progenitors in the bone marrow (BM). However, the role of histamine in hematopoiesis is not well described. To evaluate the role of histamine in hematopoiesis, we analyzed the changes in HDC expression at hematopoietic sites, the BM, spleen, and liver of 2-, 3-, and 6-week-old wild-type mice. We also performed morphological analyses of the hematopoietic sites using HDC-deficient (HDC-KO) mice. In wild-type adults, HDC expression in the BM was higher than that in the spleen and liver and showed an age-dependent increase. Histological analysis showed no significant change in the adult BM and spleen of HDC-KO mice compared to wild-type mice. In the liver, HDC expression was temporarily increased at 3 weeks and decreased at 6 weeks of age. Morphological analysis of the liver revealed more numerous hematopoietic colonies and megakaryocytes in HDC-KO mice compared to wild-type mice at 2 and 3 weeks of age, whereas no changes were observed in adults. Most of these hematopoietic colonies consisted of B220-positive B-lymphocytes and TER119-positive erythroblasts and were positive for the cell proliferation marker PCNA. Notably, these hematopoietic colonies declined in HDC-KO mice upon N-acetyl histamine treatment. A significant increase in the expression of hematopoiesis-related cytokines, Il3, Il7, Epo, Gcsf, and Cxcl12 mRNA was observed in the liver of 3-week-old HDC-KO mice compared to wild-type mice. These results suggest that histamine-deficiency may maintain an microenvironment suitable for hematopoiesis by regulating hematopoiesis-related cytokine expression in the liver of postnatal mice.

The interplay between mast cells, pineal gland, and circadian rhythm: Links between histamine, melatonin, and inflammatory mediators.

Our daily rhythmicity is controlled by a circadian clock with a specific set of genes located in the suprachiasmatic nucleus in the hypothalamus. Mast cells (MCs) are major effector cells that play a protective role against pathogens and inflammation. MC distribution and activation are associated with the circadian rhythm via two major pathways, IgE/FcεRI- and IL-33/ST2-mediated signaling. Furthermore, there is a robust oscillation between clock genes and MC-specific genes. Melatonin is a hormone derived from the amino acid tryptophan and is produced primarily in the pineal gland near the center of the brain, and histamine is a biologically active amine synthesized from the decarboxylation of the amino acid histidine by the L-histidine decarboxylase enzyme. Melatonin and histamine are previously reported to modulate circadian rhythms by pathways incorporating various modulators in which the nuclear factor-binding near the κ light-chain gene in B cells, NF-κB, is the common key factor. NF-κB interacts with the core clock genes and disrupts the production of pro-inflammatory cytokine mediators such as IL-6, IL-13, and TNF-α. Currently, there has been no study evaluating the interdependence between melatonin and histamine with respect to circadian oscillations in MCs. Accumulating evidence suggests that restoring circadian rhythms in MCs by targeting melatonin and histamine via NF-κB may be promising therapeutic strategy for MC-mediated inflammatory diseases. This review summarizes recent findings for circadian-mediated MC functional roles and activation paradigms, as well as the therapeutic potentials of targeting circadian-mediated melatonin and histamine signaling in MC-dependent inflammatory diseases.

Theanine, Antistress Amino Acid in Tea Leaves, Causes Hippocampal Metabolic Changes and Antidepressant Effects in Stress-Loaded Mice.

By comprehensively measuring changes in metabolites in the hippocampus of stress-loaded mice, we investigated the reasons for stress vulnerability and the effect of theanine, i.e., an abundant amino acid in tea leaves, on the metabolism. Stress sensitivity was higher in senescence-accelerated mouse prone 10 (SAMP10) mice than in normal ddY mice when these mice were loaded with stress on the basis of territorial consciousness in males. Group housing was used as the low-stress condition reference. Among the statistically altered metabolites, depression-related kynurenine and excitability-related histamine were significantly higher in SAMP10 mice than in ddY mice. In contrast, carnosine, which has antidepressant-like activity, and ornithine, which has antistress effects, were significantly lower in SAMP10 mice than in ddY mice. The ingestion of theanine, an excellent antistress amino acid, modulated the levels of kynurenine, histamine, and carnosine only in the stress-loaded SAMP10 mice and not in the group-housing mice. Depression-like behavior was suppressed in mice that had ingested theanine only under stress loading. Taken together, changes in these metabolites, such as kynurenine, histamine, carnosine, and ornithine, were suggested to be associated with the stress vulnerability and depression-like behavior of stressed SAMP10 mice. It was also shown that theanine action appears in the metabolism of mice only under stress loading.

Characterization of a novel enzyme from Photobacterium phosphoreum with histidine decarboxylase activity.

Histamine or scombrotoxin fish poisoning is caused by ingestion of bacterially produced histamine in fish. Histamine-producing bacteria generally contain the histidine decarboxylase gene (hdc). However, some strains of Photobacterium phosphoreum are known to produce significant levels of histamine, although the hdc gene in these strains has not been recognized. The objective of this study was to investigate a previously unidentified mechanism of histamine production by P. phosphoreum. We identified a protein with histidine decarboxylase (HDC) activity comparable to activity of the pyridoxal-5-phosphate (PLP) dependent HDC from P. kishitanii and M. morganii. The newly identified protein (HDC2) in P. phosphoreum and P. kishitanii strains, was approximately 2× longer than the HDC protein from other Gram-negative bacteria and had 12% similarity to previously identified HDCs. In addition, the hdc2 gene cluster in P. phosphoreum was identical to the hdc gene cluster in P. kishitanii. HDC2 had optimal activity at 20-35 °C, at pH 4, and was not affected by 0-8% NaCl concentrations. Compared to the hdc gene from P. kishitanii, expression of the hdc2 gene was constitutive and not affected by pH or excess histidine. This newly identified protein explains possible mechanisms of histamine production in P. phosphoreum. Characterization of this protein will help in designing control measures to prevent or reduce histamine production in fish.

How Relevant Are Bone Marrow-Derived Mast Cells (BMMCs) as Models for Tissue Mast Cells? A Comparative Transcriptome Analysis of BMMCs and Peritoneal Mast Cells.

Bone marrow-derived mast cells (BMMCs) are often used as a model system for studies of the role of MCs in health and disease. These cells are relatively easy to obtain from total bone marrow cells by culturing under the influence of IL-3 or stem cell factor (SCF). After 3 to 4 weeks in culture, a nearly homogenous cell population of toluidine blue-positive cells are often obtained. However, the question is how relevant equivalents these cells are to normal tissue MCs. By comparing the total transcriptome of purified peritoneal MCs with BMMCs, here we obtained a comparative view of these cells. We found several important transcripts that were expressed at very high levels in peritoneal MCs, but were almost totally absent from the BMMCs, including the major chymotryptic granule protease Mcpt4, the neurotrophin receptor Gfra2, the substance P receptor Mrgprb2, the metalloprotease Adamts9 and the complement factor 2 (C2). In addition, there were a number of other molecules that were expressed at much higher levels in peritoneal MCs than in BMMCs, including the transcription factors Myb and Meis2, the MilR1 (Allergin), Hdc (Histidine decarboxylase), Tarm1 and the IL-3 receptor alpha chain. We also found many transcripts that were highly expressed in BMMCs but were absent or expressed at low levels in the peritoneal MCs. However, there were also numerous MC-related transcripts that were expressed at similar levels in the two populations of cells, but almost absent in peritoneal macrophages and B cells. These results reveal that the transcriptome of BMMCs shows many similarities, but also many differences to that of tissue MCs. BMMCs can thereby serve as suitable models in many settings concerning the biology of MCs, but our findings also emphasize that great care should be taken when extrapolating findings from BMMCs to the in vivo function of tissue-resident MCs.

A single amino acid substitution converts a histidine decarboxylase to an imidazole acetaldehyde synthase.

Histidine decarboxylase (HDC; EC 4.1.1.22), an enzyme that catalyzes histamine synthesis with high substrate specificity, is a member of the group II pyridoxal 5'-phosphate (PLP) -dependent decarboxylase family. Tyrosine is a conserved residue among group II PLP-dependent decarboxylases. Human HDC has a Y334 located on a catalytically important loop at the active site. In this study, we demonstrated that a HDC Y334F mutant is capable of catalyzing the decarboxylation-dependent oxidative deamination of histidine to yield imidazole acetaldehyde. Replacement of the active-site Tyr with Phe in group II PLP-dependent decarboxylases, including mammalian aromatic amino acid decarboxylase, plant tyrosine/DOPA decarboxylase, and plant tryptophan decarboxylase, is expected to result in the same functional change, given that a Y-to-F substitution at the corresponding residue (number 260) in the HDC of Morganella morganii, another group II PLP-dependent decarboxylase, yielded the same effect. Thus, it was suggested that the loss of the OH moiety from the active-site Tyr residue of decarboxylase uniquely converts the enzyme to an aldehyde synthase.

Peroxisome proliferator-activated receptor α agonist-induced histidine decarboxylase gene expression in the rat and mouse liver.

By analysis of the data from the Toxicogenomics Database (TG-GATEs), histidine decarboxylase gene (Hdc) was identified as largely and commonly upregulated by three fibrates, clofibrate, fenofibrate, and WY-14,643, which are known to induce hepatocellular hypertrophy and proliferation via stimulation of peroxisome proliferator-activated receptor α (PPARα) in rodents. As histamine has been reported to be involved in the proliferation of liver cells, the present study was conducted to focus on Hdc. Among other genes related to histidine and histamine, the expression of the gene of histamine ammonia lyase (Hal) was exclusively mobilized by the three fibrates. The expression of Hdc, which was usually very low in the liver, was increased with the repeated administration of fibrates, and concomitantly, the constitutive expression of Hal was suppressed. An interpretation is that the formation of urocanic acid from histidine under the normal condition switches to the formation of histamine. The mobilization of gene expression of Hdc and Hal by PPARα agonists could not be reproduced in primary cultured hepatocytes. The Hdc mRNA appeared to be translated to a protein which is processed differently from brain but similarly to gastric mucosa. Surprisingly, the fibrates caused hepatic hypertrophy but no induction of Hdc mRNA at all in mice. These results revealed that the changes in the histidine catabolism by PPARα agonists might be partially, but not directly, involved in the hepatocyte proliferation in rats, and there is a large genetic distance even between rat and mouse.