Evaluation of the individual detoxification potential in the firefighters and rescuers of emercom of Russia

Relevance. Professional activities of firefighters and rescuers are usually associated with aggressive chemical exposure with increased physical exertion and psychological stress. Therefore, for professional selection and monitoring the health status of firefighters and rescuers of EMERCOM of Russia it is necessary to evaluate the activity of cytochrome P450 isoenzymes that are directly involved in detoxification pathways in the liver.

Intention. To evaluate the activity of the CYP3A4 enzyme by phenotyping methods and to establish the frequency of allelic variants of the gene of this enzyme (rs2740574 and rs4987161 polymorphisms) in firefighters and rescuers of EMERCOM of Russia for targeted treatment, rehabilitation and prevention.

Methodology. Polymorphisms (rs2740574 and rs4987161) of the CYP3A4 gene and also CYP3A4 activity by the ratio of 6-β-hydroxycortisol / cortisol in the urine were determined during routine periodical medical examination of 64 rescuers and firefighters of rescue units of EMERCOM of Russia. The average age of examined persons was (29.8 ± 5.5) years; 30 of them are rescuers of the North-West Regional Search and Rescue Squad and 34 are firefighters of the territorial fire departments of St. Petersburg.

Results and Discussion. According to the results of genotyping of rs2740574 polymorphism of the CYP3A4 gene, EMERCOM employees were divided into 2 groups depending on the presence or absence of a minor allele: “poor” and “rapid” metabolizers (9.4% and 80.6%, respectively). According to the results of genotyping of the rs4987161 polymorphism of the CYP3A4 gene, the examined were classified as “rapid” metabolizers, because patients with a minor allele were not identified. Depending on the ratio of 6-β-hydroxycortisol / cortisol in the urine, the activity level of CYP3A4 was “normal” in 67 %, “poor” in 13 % and “rapid” in 20 % of cases. The ratio of 6-β-hydroxycortisol / cortisol in the urine tended to increase with an increase in work experience and age. No relationship between the studied polymorphic variants of the CYP3A4 gene and the established enzyme activity was observed.

Conclusion. Genotyping methods made it possible to identify allelic variants of the CYP3A4 gene that could affect the functionality of the enzyme; however, no association of the studied polymorphisms with enzyme activity was found. In such cases, in the absence of informative genetic markers, it is recommended to evaluate the enzyme activity by phenotyping methods.

1. Abdrashitov R.KH., Gil’deyeva G.N., Ramenskaya G.V. [et al.]. Obzor sushchestvuyushchikh metodik otsenki aktivnosti CYP2D6 s primeneniyem ekzogennykh i endogennykh markerov [A review of existing methods for assessing the activity of CYP2D6 using exogenous and endogenous markers]. Farmakokinetika i farmakodinamika [Pharmacokinetics and pharmacodynamics]. 2015. N 1. Pp. 4–11. (In Russ.)

2. Kukes V.G. Metabolizm lekarstvennykh sredstv: kliniko-farmakologicheskiye aspekty [Drug metabolism: clinical and pharmacological aspects]. Moskva. 2004. 144 p. (In Russ.)

3. Mustafina O.Ye., Tuktarova I.A., Karimov D.D. [et al.]. Polimorfizm genov CYP2D6, CYP3A5 i CYP3A4 v populyatsiyakh russkikh, tatar i bashkir [CYP2D6, CYP3A5 and CYP3A4 gene polymorphisms in populations of Russians, Tatars and Bashkirs] Genetika [Genetics]. 2015. Vol. 51, N 1. Pp. 109–119. (In Russ.)

4. Smirnov V.V. Razrabotka metodiki opredeleniya kortizola i 6-b-gidroksikortizola v moche s tsel’yu ustanovleniya aktivnosti izofermenta CYP 3A4 [Development of a method for determination of cortisol and 6-β-hydroxycortisol in urine in order to establish the activity of the CYP 3A4 isoenzyme]: Abstract dissertation PhD pharm. Sci. Moskva. 2011. 24 p. (In Russ.)

5. Sychev D.A. Rekomendatsii dlya farmatsevticheskikh kompaniy po izucheniyu biotransformatsii i transporterov novykh lekarstvennykh sredstv: dizayn issledovaniy, analiz dannykh i vneseniye informatsii v instruktsii po primeneniyu [Recommendations for pharmaceutical companies for the study of biotransformation and transporters of new drugs: research design, data analysis and entering information in the instructions for use]. Ed. V.G. Kukes. Moskva. 2009. (In Russ.) URL: http://www.regmed.ru/Content/Doc.aspx?id=26a9128c-ee32-4469-9c64-5c666339049e. (In Russ.)

6. Formirovaniye standarta diagnostiki oksidativnogo stressa pri obsledovanii sotrudnikov GPS MCHS Rossii [Formation of a standard for the diagnosis of oxidative stress during the medical examination of employees of the State Fire Service of the EMERCOM of Russia]. Ed. S.S. Aleksanin. St. Petersburg. 2019. 40 p. (In Russ.)

7. Drogemoller B., Plummer M., Korkie L. [et al.]. Characterization of the genetic variation present in CYP3A4 in three South African populations. Front. Genet. 2013. Vol. 4, N 17. DOI: 10.3389/fgene.2013.00017.

8. McGraw J., Waller D. Cytochrome P450 variations in different ethnic populations. Expert. Opin. Drug. Metab. Toxicol. 2012. Vol. 8, N 3. Pp. 371–382. DOI: 10.1517/17425255.2012.657626.

9. Preskorn S.H. [et al.]. Cytochrome P450 2D6 Phenoconversion Is Common in Patients Being Treated for Depression: Implications for Personalized Medicine. J. Clin. Psychiatry. 2013. Vol. 74, N 6. Pp. 614–621. DOI: 10.4088/JCP.12m07807.

10. Werk A. N., Cascorbi I. Functional gene variants of CYP3A4. Clin. Pharmacol. 2014. Vol. 96, N 3. Pp. 340–348. DOI: 10.1038/clpt.2014.129

11. Zhou L.P., Yao F., Luan H. [et al.]. CYP3A4*1B polymorphism and cancer risk: a HuGE review and meta-analysis. Tumour Biol. 2013. Vol. 34, N 2. Pp. 649–660. DOI: 10.1007/s13277-012-0592-z.