mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2016-1-41-50mimmun-987Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESАНТИТЕЛА ПРОТИВ БЕНЗО[А]ПИРЕНА И ПОЛИМОРФИЗМ CYP1A1*2A, CYP1A2*1F, GSTT1, GSTM1 У ЗДОРОВЫХ МУЖЧИН И БОЛЬНЫХ РАКОМ ЛЕГКОГОANTIBODIES TO BENZO[A]PYRENE AND POLYMORPHISMS OF CYP1A1*2A, CYP1A2*1F, GSTT1, AND GSTM1 GENES IN HEALTHY MEN AND LUNG CANCER PATIENTSГлушковА. Н.GlushkovA. N.

д.м.н., профессор, директор;

профессор кафедры генетики биологического факультета,

г. Кемерово

PhD, MD (Medicine), Professor, Department of Genetics, Faculty of Biology;

Department of Molecular Human Ecology,

Kemerovo

ПоленокЕ. Г.PolenokE. G.

к.фарм.н., заведующая лабораторией иммунохимии,

650065, г. Кемерово, пр. Ленинградский, 10

PhD (Pharmacy), Chief, Laboratory of Immunochemistry, Department of Molecular Human Ecology

650065, Kemerovo, Leningradskiy av., 10

egpolenok@mail.ruГордееваЛ. А.GordeevaL. A.

к.б.н., заведующая лабораторией иммуногенетики,

г. Кемерово

PhD (Biology), Chief Laboratory of Immunogenetics, Department of Molecular Human Ecology,

Kemerovo

МунС. А.MunS. A.

к.м.н., старший научный сотрудник лаборатории иммуногенетики,

г. Кемерово

PhD (Medicine), Senior Research Associate, Laboratory of Immunogenetics, Department of Molecular Human Ecology,

Kemerovo

ТитовВ. А.TitovV. A.

заведующий торакальным отделением,

г. Кемерово

Chief, Thoracic Department,

Kemerovo

КостянкоМ. В.KostyankoM. V.

ведущий инженер кафедры органической химии,

г. Кемерово

Leading Engineer, Department of Organic Chemistry,

Kemerovo

ВафинИ. А.VafinI. A.

главный врач,

г. Кемерово

Physician-In-Chief,

Kemerovo

РагожинаС. Е.RagozhinaS. E.

заместитель главного врача по медицинской части,

г. Кемерово

Deputy Chief Physician for Medicine,

Kemerovo

ФГБУН «Институт экологии человека» СО РАН; ФГБОУ ВПО «Кемеровский государственный университет»РоссияKemerovo State University; Institute of Human Ecology Siberian Branch of Russian Academy of SciencesRussian FederationФГБУН «Институт экологии человека» СО РАНРоссияInstitute of Human Ecology Siberian Branch of Russian Academy of SciencesRussian FederationГБУЗ КО «Областной клинический онкологический диспансер»РоссияRegional Clinical Oncology DispensaryRussian FederationФГБОУ ВПО «Кемеровский государственный университет»РоссияKemerovo State UniversityRussian FederationГКУЗ КО «Кемеровский областной центр крови»РоссияRegional Blood BankRussian Federation2016130420161814150Copyright © Глушков А.Н., Поленок Е.Г., Гордеева Л.А., Мун С.А., Титов В.А., Костянко М.В., Вафин И.А., Рагожина С.Е., 20162016Глушков А.Н., Поленок Е.Г., Гордеева Л.А., Мун С.А., Титов В.А., Костянко М.В., Вафин И.А., Рагожина С.Е.Glushkov A.N., Polenok E.G., Gordeeva L.A., Mun S.A., Titov V.A., Kostyanko M.V., Vafin I.A., Ragozhina S.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/987

Известно, что генетический полиморфизм ферментов биотрансформации низкомолекулярных ксенобиотиков CYP, GST является одним из эндогенных факторов канцерогенеза. Вместе с тем взаимосвязи между активностью ферментов биотрансформации, количеством канцерогенных аддуктов и образованием антиканцерогенных антител у человека, в том числе при онкологических заболеваниях, до сих пор остаются мало изученными.

Цель исследования – выявить возможные ассоциации образования антител против бензо[а]пирена с генетическими полиморфизмами CYP1A1*2A, CYP1A2*1F, GSTT1, GSTM1 у здоровых мужчин и больных раком легкого.

Были обследованы 203 мужчины с немелкоклеточной формой рака легкого и 267 условно здоровых доноров без патологии органов дыхания. Иммуноанализ антител к бензо[a]пирену был выполнен с помощью твердофазного неконкурентного иммуноферментного анализа. Типирование полиморфных локусов CYP1A1 (rs4646903), CYP1A2 (rs762551), GSTP1 (rs1695, rs1138272) проводили методом Real-time ПЦР с использованием технологии конкурирующих TaqMan-зондов, генов GSTM1(del), GSTT1(del) методом мультиплексной ПЦР с флуоресцентной детекцией продуктов в режиме Real-time.

У больных раком легкого доля случаев с высоким уровнем IgG антител к бензо[a]пирену у носите- лей GSTT1«+» и GSTM1«+» в сочетании с аллелем С CYP1A2*1F была статистически значимо больше, чем у гомозигот АА CYP1A2*1F. У носителей аллеля С CYP1A2*1F в сочетании с GSTT1«+» и GSTM1«+» при высоких уровнях IgG антител к бензо[a]пирену риск рака легкого возрастал до 5.5. У здоровых мужчин – носителей отдельных генотипов CYP1A1*2А, CYP1A2*1F, GSTT1 и GSTM1 разницы в частоте встречаемости низких и высоких уровней IgG антител к бензо[a]пирену не выявлено.

Впервые обнаружены взаимосвязи специфической иммунной реакции на химические канцерогены окружающей среды с полиморфизмом генов ферментов биотрансформации низкомолекулярных ксенобиотиков у больных раком легкого. Показана высокая информативность иммуноанализа IgG антител к бензо[a]пирену в сочетании с молекулярно-генетическим анализом CYP1 и GST для определения риска рака легкого.

Some genetic polymorphisms of CYP and GST enzymes metabolizing low-molecular weight xenobiotics may represent endogenous risk factors for carcinogenesis. However, possible relationships between the enzyme activities, amounts of carcinogen adducts and synthesis of anticarcinogen antibodies in humans (including cancer patients) are still poorly studied. The purpose of this study was to identify possible associations between occurrence of antibodies against benzo[a]pyrene, and frequency of genetic polymorphisms of CYP1A1*2A, CYP1A2*1F, GSTT1, GSTM1 in healthy men and in lung cancer patients. Materials and methods. We have examined 203 men with non-small cell lung cancer and 267 apparently healthy donors without respiratory diseases. A non-competitive solid phase immunoassay of antibodies to benzo[a]pyrene was performed. Analysis of polymorphic loci within CYP1A1 (rs4646903), CYP1A2 (rs762551), GSTP1 (rs1695, rs1138272) was performed by means of real-time PCR using TaqMan technology. Null-alleles of GSTM1 (del), GSTT1 (del) genes were detected by multiplex PCR with real-time fluorescent assay. Results. Among the lung cancer patients, the proportion of cases with a high level of IgG antibodies to benzo[a]pyrene in carriers of GSTT1+ and GSTM1+ in conjunction with the CYP1A2*1F C allele was significantly greater than in AA homozygotes CYP1A2*1F. The risk of lung cancer was increased to 5.5 in carriers of CYP1A2*1F C allele combined with GSTT1+ and GSTM1+ at high levels of IgG antibodies to benzo [a] pyrene. In healthy male donors, we have not found differences between the incidence of low and high levels of IgG anti-benzo[a]pyrene antibodies in the carriers of certain CYP1A1*2A, CYP1A2*1F, GSTT1 and GSTM1 genotypes. Conclusions. We have first reported a relationship between CYP1 and GST gene polymorphisms and specific immune response to chemical carcinogens in lung cancer patients. Immunoassays of IgG antibodies to benzo[a]pyrene combined with molecular biology studies of CYP1 and GST are recommended for the cancer risk assessment.

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The authors declare that there are no conflicts of interest present.