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2018•Pharmacogenomics and Personalized MedicineOpen access

CYP3A and CYP2C19 activity in urine in relation to CYP3A4, CYP3A5, and CYP2C19 polymorphisms in Russian peptic ulcer patients taking omeprazole

Н. П. Денисенко, Dmitry Alekseevich Sychev, Zhanna M. Sizova, Smirnov Vv, Kristina Ryzhikova, Zhannet Alimovna Sozaeva, Е. А. Гришина

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Abstract

Background: Proton pump inhibitors (PPIs) are metabolized by cytochrome P450. CYP2C19 is the main isoenzyme for the majority of PPI, whereas CYP3A family is a secondary enzyme for PPI biotransformation. Purpose: The aim of the study was to find if CYP3A4*22 , CYP3A5*3 , CYP2C19*2 , CYP2C19*3 , and CYP2C19*17 genotypes are connected with CYP3A and CYP2C19 activities in Russian peptic ulcer patients taking omeprazole. Patients and methods: Forty-eight gastric or duodenal ulcer patients (15 men, 33 women; mean age 55.0±15.3 years, age range 18–91 years) from Moscow region of Russia were enrolled. Peripheral venous blood was collected for DNA extraction, and real-time polymerase chain reaction was performed for CYP3A5*3 A6986G (rs776746), CYP3A4*22 C>T in intron 6 (rs35599367), CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893), and CYP2C19*17C-806T (rs12248560) polymorphism analyses. Urine samples of patients were collected in the morning between 6 and 9 am before food or drug intake. Urine cortisol and 6β-hydroxycortisol concentrations (for CYP3A activity) and omeprazole and 5-hydroxyomeprazole concentrations (for CYP2C19 activity) were measured using high-performance liquid chromatography/mass spectroscopy. Results: We found a connection between CYP2C19 genotypes and CYP3A activity. Median metabolic ratios 6β-hydroxycortisol/cortisol (25%–75% percentiles) were 2.84 (1.99–4.39) for CYP2C19 extensive metabolizers (EMs), 2.51 (1.86–4.73) for CYP2C19 ultra-rapid metabolizers (UMs), and 1.45 (1.12–2.16) for CYP2C19 intermediate metabolizers (IMs) + poor metabolizers (PMs). A statistically significant difference in CYP3A activity (Mann–Whitney test) was found between CYP2C19 EMs vs CYP2C19 IMs+PMs ( p =0.006), between CYP2C19 UMs vs CYP2C19 IMs+PMs ( p =0.018), and in multiple comparison Kruskal–Wallis test ( p =0.014). Conclusion: In CYP2C19 IMs+PMs, CYP3A activity was significantly lower than in CYP2C19 EMs and UMs. Keywords: pharmacogenetics, phenotyping, metabolomics, proton pump inhibitor

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Background: Proton pump inhibitors (PPIs) are metabolized by cytochrome P450. CYP2C19 is the main isoenzyme for the majority of PPI, whereas CYP3A family is a secondary enzyme for PPI biotransformation. Purpose: The aim of the study was to find if CYP3A4*22 , CYP3A5*3 , CYP2C19*2 , CYP2C19*3 , and CYP2C19*17 genotypes are connected with CYP3A and CYP2C19 activities in Russian peptic ulcer patients taking omeprazole. Patients and methods: Forty-eight gastric or duodenal ulcer patients (15 men, 33 women; mean age 55.0±15.3 years, age range 18–91 years) from Moscow region of Russia were enrolled. Peripheral venous blood was collected for DNA extraction, and real-time polymerase chain reaction was performed for CYP3A5*3 A6986G (rs776746), CYP3A4*22 C>T in intron 6 (rs35599367), CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893), and CYP2C19*17C-806T (rs12248560) polymorphism analyses. Urine samples of patients were collected in the morning between 6 and 9 am before food or drug intake. Urine cortisol and 6β-hydroxycortisol concentrations (for CYP3A activity) and omeprazole and 5-hydroxyomeprazole concentrations (for CYP2C19 activity) were measured using high-performance liquid chromatography/mass spectroscopy. Results: We found a connection between CYP2C19 genotypes and CYP3A activity. Median metabolic ratios 6β-hydroxycortisol/cortisol (25%–75% percentiles) were 2.84 (1.99–4.39) for CYP2C19 extensive metabolizers (EMs), 2.51 (1.86–4.73) for CYP2C19 ultra-rapid metabolizers (UMs), and 1.45 (1.12–2.16) for CYP2C19 intermediate metabolizers (IMs) + poor metabolizers (PMs). A statistically significant difference in CYP3A activity (Mann–Whitney test) was found between CYP2C19 EMs vs CYP2C19 IMs+PMs ( p =0.006), between CYP2C19 UMs vs CYP2C19 IMs+PMs ( p =0.018), and in multiple comparison Kruskal–Wallis test ( p =0.014). Conclusion: In CYP2C19 IMs+PMs, CYP3A activity was significantly lower than in CYP2C19 EMs and UMs. Keywords: pharmacogenetics, phenotyping, metabolomics, proton pump inhibitor

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Available abstract

Background: Proton pump inhibitors (PPIs) are metabolized by cytochrome P450. CYP2C19 is the main isoenzyme for the majority of PPI, whereas CYP3A family is a secondary enzyme for PPI biotransformation. Purpose: The aim of the study was to find if CYP3A4*22 , CYP3A5*3 , CYP2C19*2 , CYP2C19*3 , and CYP2C19*17 genotypes are connected with CYP3A and CYP2C19 activities in Russian peptic ulcer patients taking omeprazole. Patients and methods: Forty-eight gastric or duodenal ulcer patients (15 men, 33 women; mean age 55.0±15.3 years, age range 18–91 years) from Moscow region of Russia were enrolled. Peripheral venous blood was collected for DNA extraction, and real-time polymerase chain reaction was performed for CYP3A5*3 A6986G (rs776746), CYP3A4*22 C>T in intron 6 (rs35599367), CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893), and CYP2C19*17C-806T (rs12248560) polymorphism analyses. Urine samples of patients were collected in the morning between 6 and 9 am before food or drug intake. Urine cortisol and 6β-hydroxycortisol concentrations (for CYP3A activity) and omeprazole and 5-hydroxyomeprazole concentrations (for CYP2C19 activity) were measured using high-performance liquid chromatography/mass spectroscopy. Results: We found a connection between CYP2C19 genotypes and CYP3A activity. Median metabolic ratios 6β-hydroxycortisol/cortisol (25%–75% percentiles) were 2.84 (1.99–4.39) for CYP2C19 extensive metabolizers (EMs), 2.51 (1.86–4.73) for CYP2C19 ultra-rapid metabolizers (UMs), and 1.45 (1.12–2.16) for CYP2C19 intermediate metabolizers (IMs) + poor metabolizers (PMs). A statistically significant difference in CYP3A activity (Mann–Whitney test) was found between CYP2C19 EMs vs CYP2C19 IMs+PMs ( p =0.006), between CYP2C19 UMs vs CYP2C19 IMs+PMs ( p =0.018), and in multiple comparison Kruskal–Wallis test ( p =0.014). Conclusion: In CYP2C19 IMs+PMs, CYP3A activity was significantly lower than in CYP2C19 EMs and UMs. Keywords: pharmacogenetics, phenotyping, metabolomics, proton pump inhibitor

Key concepts: CYP2C19, Omeprazole, Medicine, CYP3A4, CYP3A5, CYP3A, Gastroenterology, Peptic ulcer

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CYP3A and CYP2C19 activity in urine in relation to CYP3A4, CYP3A5, and CYP2C19 polymorphisms in Russian peptic ulcer patients taking omeprazole — Research Paper | ScholarLens