Effect of CYP3A5*3 on asthma control among children treated with inhaled beclomethasone

Reilly, Christopher A.; Fassl, Bernhard; Gaedigk, Roger; Nkoy, Flory L.; Stone, Bryan L.; Roberts, Jessica K.; Uchida, Derek A.; Leeder, J. Steven; Sherwin, Catherine M.T.; Spigarelli, Michael G.; Yost, Garold S.; Ward, Robert M.

doi:10.1016/j.jaci.2015.02.009

Cited by 20 publications

(25 citation statements)

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“…St. Helens volcanic ash, and urban particles collected in Salt Lake City, UT; St. Louis, MO; and Ottawa, Canada (12)(13)(14)(15). CFA and other insoluble PM preferentially activate TRPV1 at the cell surface independent of the capsaicin-binding site (12,16). C-fiber activation by TRPA1 and TRPV1 agonists reduces respiratory drive, induces cough, and triggers bronchoconstriction and neurogenic inflammation (17).…”

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confidence: 99%

Characterization of Transient Receptor Potential Vanilloid-1 (TRPV1) Variant Activation by Coal Fly Ash Particles and Associations with Altered Transient Receptor Potential Ankyrin-1 (TRPA1) Expression and Asthma

Deering-Rice

Romero

et al. 2016

Journal of Biological Chemistry

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Transient receptor potential (TRP) channels are activated by environmental particulate materials. We hypothesized that polymorphic variants of transient receptor potential vanilloid-1 (TRPV1) would be uniquely responsive to insoluble coal fly ash compared with the prototypical soluble agonist capsaicin. Furthermore, these changes would manifest as differences in lung cell responses to these agonists and perhaps correlate with changes in asthma symptom control. The TRPV1-I315M and -T469I variants were more responsive to capsaicin and coal fly ash. The I585V variant was less responsive to coal fly ash particles due to reduced translation of protein and an apparent role for Ile-585 in activation by particles. In HEK-293 cells, I585V had an inhibitory effect on wild-type TRPV1 expression, activation, and internalization/agonist-induced desensitization. In normal human bronchial epithelial cells, IL-8 secretion in response to coal fly ash treatment was reduced for cells heterozygous for TRPV1-I585V. Finally, both the I315M and I585V variants were associated with worse asthma symptom control with the effects of I315M manifesting in mild asthma and those of the I585V variant manifesting in severe, steroid-insensitive individuals. This effect may be due in part to increased transient receptor potential ankyrin-1 (TRPA1) expression by lung epithelial cells expressing the TRPV1-I585V variant. These findings suggest that specific molecular interactions control TRPV1 activation by particles, differential activation, and desensitization of TRPV1 by particles and/or other agonists, and cellular changes in the expression of TRPA1 as a result of I585V expression could contribute to variations in asthma symptom control.

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confidence: 99%

Characterization of Transient Receptor Potential Vanilloid-1 (TRPV1) Variant Activation by Coal Fly Ash Particles and Associations with Altered Transient Receptor Potential Ankyrin-1 (TRPA1) Expression and Asthma

Deering-Rice

Romero

et al. 2016

Journal of Biological Chemistry

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“…Ранее проведенные фармакогенетические исследования продемонстрировали влияние полиморфизмов генов, ответственных за работу изоферментов цитохрома Р450, на течение респираторных заболеваний, а также на эффективность и безопасность используемых при этом лекарственных средств [5,[9][10][11][12]. Имеющиеся результаты отражают необходимость таких исследований у пациентов с бронхиальной астмой.…”

Section: оригинальные статьиunclassified

Association of CYP3A5 (6986A>G) gene polymorphism with the effectiveness of anti-inflammatory therapy in children with bronchial asthma

Zastrozhina

Захарова

Сычев

et al. 2019

Ross. vestn. perinatol. pediatr.

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Inhaled glucocorticosteroids are the main drugs used to control bronchial asthma in children. P450-cytochrome of 3A (CYP3A) family is involved in their metabolism. CYP3A5-isoenzyme plays the leading role in the respiratory tract. We described 6986A>G polymorphism in the CYP3A5 gene encoding this isoenzyme.Aim of the study. To evaluate the association of CYP3A5 (6986A> G) gene polymorphism with the effectiveness of drugs in children with bronchial asthma.Materials and methods. We examined 108 children from 6 to 17 years with bronchial asthma. The allergist carried out the dynamic outpatient polyclinic follow-up of patients, assessed the symptoms of the disease and corrected the corresponding basic therapy. All children underwent genotyping for the 6986A> G polymorphic marker of the CYP3A5 gene.Results. Ten (9.26%) children were heterozygous for the 6986A> G polymorphic marker of the CYP3A5 gene (AG genotype). The authors obtained statistically significant differences in the frequency of the AG genotype between the patients receiving control therapy for bronchial asthma of the 1st – 2nd stage and the patients with control therapy of the 3rd and higher stages in accordance with GINA criteria (p=0.031). In the group with severe bronchial asthma, the number of heterozygotes for the 6986A> G polymorphic marker of the CYP3A5 gene was significantly higher than among children with a mild course of the disease (p=0.029).Conclusion. The AG genotype and A-allele (CYP3A5 gene, A6986A> G polymorphism) are associated with the need for greater volume of control therapy for bronchial asthma and they are risk factors of a more severe course of the disease.

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“…В 2015 году в исследовании у 64 детей в возрасте от 2 до 17 лет с бронхиальной астмой изучали влияние полиморфизмов генов семейства CYP3A на эффективность терапии ингаляционным беклометазона дипропионатом, которую также оценивали с помощью вопросника [30]. Два полиморфных варианта гена CYP3A5 были ассоциированы с улучшением контроля над течением бронхиальной астмы.…”

Section: изоферменты цитохрома р450unclassified

“…У пациентов с генотипом ТCYP3A5*3/*3 эффективность ингаляционного глюкокортикостероида была выше, чем у носителей генотипов CYP3A5*1/*3 и CYP3A5*1/*1. Большинство представителей европеоидной расы являются гомозиготами по полиморфному варианту CYP3A5*3, отвечающего за экспрессию неактивной формы изофермента CYP3A5 [30].…”

Section: изоферменты цитохрома р450unclassified

Pharmacogenetic aspects of the efficacy and safety of inhaled glucocorticosterois in bronchial asthma

Zastrozhina¹,

Sychev²

2018

Clin Pharmacol Ther

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Ингаляционные глюкокортикостероиды являются препаратами первой линии в базисной терапии бронхиальной астмы, а также могут быть использованы для купирования обострений заболевания. В метаболизме ингаляционных глюкокортикостероидов принимают участие изоферменты цитохрома Р450 семейства 3А, синтез которых кодируется генами, имеющими высокую степень полиморфизма. Кроме того, глюкокортикостероиды являются субстратами Р-гликопротеина, кодируемого геном множественной лекарственной устойчивости, который также обладает высокой степенью полиморфизма. Изменение уровня метаболизма ингаляционных глюкокортикостероидов, а также их активного транспорта через клеточную мембрану может оказывать влияние на эффективность и безопасность этих лекарственных средств. В настоящее время проводится поиск других возможных геновкандидатов, которые на том или ином этапе могут повлиять на действие ингаляционных глюкокортикостероидов. Целью данного обзора было обобщить имеющуюся информацию о фармакогенетических особенностях ингаляционных глюкокортикостероидов и механизмах межиндивидуальной вариабельности их эффективности и безопасности в терапии бронхиальной астмы.Ключевые слова. Фармакогенетика, ингаляционные глюкокортикостероиды, цитохром Р450, бронхиальная астма.

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Effect of CYP3A5*3 on asthma control among children treated with inhaled beclomethasone

Cited by 20 publications

References 11 publications

Characterization of Transient Receptor Potential Vanilloid-1 (TRPV1) Variant Activation by Coal Fly Ash Particles and Associations with Altered Transient Receptor Potential Ankyrin-1 (TRPA1) Expression and Asthma

Characterization of Transient Receptor Potential Vanilloid-1 (TRPV1) Variant Activation by Coal Fly Ash Particles and Associations with Altered Transient Receptor Potential Ankyrin-1 (TRPA1) Expression and Asthma

Association of CYP3A5 (6986A>G) gene polymorphism with the effectiveness of anti-inflammatory therapy in children with bronchial asthma

Pharmacogenetic aspects of the efficacy and safety of inhaled glucocorticosterois in bronchial asthma

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