Tổng quan về phân tích acid amin trong dịch sinh học phục vụ chẩn đoán và điều trị một số bệnh

BỘ Y TẾ TRƢỜNG ĐẠI HỌC DƢỢC HÀ NỘI PHAN THỊ NGÂN GIANG TỔNG QUAN VỀ PHÂN TÍCH ACID AMIN TRONG DỊCH SINH HỌC PHỤC VỤ CHẨN ĐOÁN VÀ ĐIỀU TRỊ MỘT SỐ BỆNH KHÓA LUẬN TỐT NGHIỆP DƢỢC SĨ HÀ NỘI - 2020 BỘ Y TẾ TRƢỜNG ĐẠI HỌC DƢỢC HÀ NỘI PHAN THỊ NGÂN GIANG MÃ SINH VIÊN: 1501129 TỔNG QUAN VỀ PHÂN TÍCH ACID AMIN TRONG DỊCH SINH HỌC PHỤC VỤ CHẨN ĐOÁN VÀ ĐIỀU TRỊ MỘT SỐ BỆNH KHÓA LUẬN TỐT NGHIỆP DƢỢC SĨ Người hướng dẫn : ThS Vũ Ngân Bình PGS.TS Phạm Thị Thanh Hà Nơi thực : Bộ mơn Hóa phân tích độc chất HÀ NỘI - 2020 Lời cảm ơn Lời đầu tiên, xin bày tỏ lòng biết ơn chân thành sâu sắc đến ThS Vũ Ngân Bình PGS.TS Phạm Thị Thanh Hà, người trực tiếp hướng dẫn, truyền đạt cho kiến thức kinh nghiệm quý báu, tận tình giúp đỡ suốt quãng thời gian thực khóa luận Tơi xin chân thành cảm ơn cảm ơn thầy cô anh chị kỹ thuật viên cơng tác mơn Hóa Phân tích Độc chất – Trường Đại học Dược Hà Nội động viên tạo điều kiện thuận lợi để giúp đỡ tơi hồn thành khóa luận Tơi xin gửi lời cảm ơn đến thầy cô quan tâm, giúp đỡ bạn bè đồng hành suốt tháng năm học tập trường Cảm ơn anh chị bạn thực khóa luận mơn Hóa Phân tích Độc chất ln gắn bỏ, chia sẻ nhau, giúp đỡ lẫn suốt khoảng thời gian thực khóa luận Cuối cùng, xin dành biết ơn sâu sắc tới bố mẹ người thân yêu gia đình yêu thương tôi, ủng hộ động viên tôi, tạo điều kiện tốt để giúp hồn thành khóa luận Do thời gian kiến thức thân cịn nhiều hạn chế, khóa luận khơng thể tránh khỏi thiếu sót Tơi mong nhận góp ý thầy bạn để khóa luận hồn thiện Tôi xin chân thành cảm ơn! Hà Nội, ngày 22 tháng 06 năm 2020 Sinh viên Phan Thị Ngân Giang MỤC LỤC DANH MỤC CHỮ VÀ KÝ HIỆU VIẾT TẮT DANH MỤC CÁC BẢNG DANH MỤC CÁC HÌNH VẼ VÀ ĐỒ THỊ ĐẶT VẤN ĐỀ CHƢƠNG TỔNG QUAN VỀ MỘT SỐ BỆNH LIÊN QUAN ĐẾN THAY ĐỔI NỒNG ĐỘ ACID AMIN TRONG MÁU VÀ NƢỚC TIỂU 1.1 Bệnh rối loạn chuyển hoá acid amin bẩm sinh 1.1.1 Rối loạn chuyển hoá acid amin thơm 1.1.1.1 Phenylketonuria (PKU) 1.1.1.2 Non-PKU hyperphenylalaninemia (HPA) 1.1.1.3 Tyrosinemia 1.1.1.4 Hawkisinuria 1.1.1.5 Alkaptonuria 1.1.2 Rối loạn chuyển hóa acid amin chuỗi nhánh 10 1.1.2.1 Bệnh siro niệu (MSUD) 11 1.1.2.2 Hypervalinemia 13 1.1.2.3 Isovaleric acidemia (IVA) 14 1.1.2.4 Giảm betaketothiolase 15 1.1.3 Rối loạn acid amin có chứa lưu huỳnh 15 1.1.3.1 Hypermethioninemia 16 1.1.3.2 Homocystinuria 18 1.1.3.3 Sulfocysteinuria 19 1.1.4 Rối loạn chuyển hóa glycin (Nonketotic Hyperglycinemia) 20 1.1.5 Một số rối loạn khác 21 1.1.5.1 Methylmalonic acidemia (MMA) 21 1.1.5.2 Propionic acidemia 23 1.1.5.3 Thiếu hụt arginase-1 (Hyperargininmia) 24 1.1.5.4 Glutaric acidemia typ I (GAI) 24 1.1.5.5 Hyperprolinemia (HPI) 25 1.2 Các bệnh khác liên quan 26 1.2.1 Béo phì rối loạn mỡ máu 27 1.2.2 Kháng insulin 27 1.2.3 Đái tháo đường 27 1.2.4 Các rối loạn thần kinh tâm thần 28 1.2.5 Ung thư 28 CHƢƠNG PHÂN TÍCH ACID AMIN TRONG DỊCH SINH HỌC VÀ ỨNG DỤNG TRONG NGHIÊN CỨU, CHẨN ĐOÁN VÀ THEO DÕI ĐIỀU TRỊ MỘT SỐ BỆNH 30 2.1 Lựa chọn loại mẫu cách lấy mẫu 30 2.1.1 Loại mẫu 30 2.1.2 Cách lấy mẫu 31 2.2 Xử lý mẫu 31 2.3 Dẫn xuất hóa 33 2.3.1 Sự cần thiết dẫn xuất hóa với acid amin 33 2.3.2 Tác nhân dẫn xuất hóa 33 2.3.3 Cách thức dẫn xuất hóa 35 2.3.3.1 Dẫn xuất hóa trước cột 35 2.3.3.2 Dẫn xuất hóa sau cột 35 2.4 Kỹ thuật phân tích 36 2.4.1 Các kỹ thuật sắc ký 36 2.4.1.1 Sắc ký lỏng pha đảo 36 2.4.1.2 Sắc ký trao đổi ion 37 2.4.1.3 Sắc ký lỏng tương tác thân nước 38 2.4.1.4 Sắc ký khí 40 2.4.2 Các loại detector dùng sắc ký 40 2.4.2.1 UV/PDA 40 2.4.2.2 Huỳnh quang 40 2.4.2.3 Khối phổ 41 2.4.3 Điện di 41 2.4.3.1 CE-UV 41 2.4.3.2 CE-LIF 42 2.4.3.3 CE-MS 43 CHƢƠNG BÀN LUẬN 46 3.1 Các bệnh chuyển hóa liên quan đến acid amin 46 3.2 Các kỹ thuật phân tích acid amin dịch sinh học 46 CHƢƠNG KẾT LUẬN VÀ ĐỀ XUẤT 48 4.1 Kết luận 48 4.2 Đề xuất 48 DANH MỤC CHỮ VÀ KÝ HIỆU VIẾT TẮT BCAA Acid amin chuỗi nhánh BCKA Ketoacid chuỗi nhánh BCKD Enzym dehydrogenase ketoacid chuỗi nhánh BDS Giọt máu khô BH4 Tetrahydrobiopterin BHMT Betain-homocystein methyltransferase BKT Bệnh giảm betaketothiolase BSTFA N,O-bis(trimethylsilyl)trifluoroacetamid CE Điện di CSF Dịch não tủy DHPR Dihydrobiopterin reductase FLD detector huỳnh quang GAI Bệnh Glutaric acidemia typ I GC Sắc ký GNMT Glycin N-methyltransferase GSC Phức hợp enzym phân cắt glycin GTPCH Guanosin triphosphat cyclohydrolase HILIC Sắc ký lỏng tương tác thân nước HPA Bệnh tăng phenylalanin không PKU HPI Bệnh Hyperprolinemia IEM Rối loạn chuyển hóa bẩm sinh IVA Bệnh Isovaleric acidemia MAT Methionin adenosyl transferase MET Bệnh Hypermethioninmia MSUD Bệnh siro niệu MTHFR Methylen tetrahydrofolat reductase MUT Methylmalonyl-CoA mutase NMDT N-methyl-D-aspartat NPLC Sắc ký lỏng pha thường NTBC 2- (2-nitro-4-trifluoro -methylbenzoyl) 1,3-cyclohexanedion PCD Pterin-4α-carbinolamin dehydratase PKU Bệnh Phenylketonuria PTPS Pyruvoyl tetrahydropterin synthase RLCH Rối loạn chuyển hóa RPLC Sắc ký lỏng pha đảo SAH S-adenosyl methionin SAHH S-adenosylhomocystein hydrolase SAM S-adenosyl methionin SSA 5-sulfosalicylic acid THF Methyl tetrahydrofolat TYR Bệnh Tyrosinemia δ-ALA δ - aminolevulinic acid DANH MỤC CÁC BẢNG Bảng 1.1 Giá trị chẩn đoán mục tiêu điều trị số bệnh 29 Bảng 3.1 Các phương pháp định lượng acid amin dịch sinh học 44 DANH MỤC CÁC HÌNH VẼ, ĐỒ THỊ Hình 1.1 Con đường chuyển hóa phenylalanin tyrosin Hình 1.2 Con đường tổng hợp tái tổng hợp BH4 Hình 1.3 Q trình chuyển hóa acid amin chuỗi nhánh 11 Hình 1.4 Quá trình chuyển hóa methionin cystein dịch sinh học 16 Hình 1.5 Q trình chuyển hóa prolin 26 Atherton Philip, Selby Anna (2008), "Disassociation 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CHƢƠNG PHÂN TÍCH ACID AMIN TRONG DỊCH SINH HỌC VÀ ỨNG DỤNG TRONG NGHIÊN CỨU, CHẨN ĐOÁN VÀ THEO DÕI ĐIỀU TRỊ MỘT SỐ BỆNH Như phân tích chương I, acid amin đóng vai trị quan trọng hoạt động sống... ? ?Tổng quan phân tích acid amin chẩn đoán theo dõi điều trị số bệnh? ?? tiến hành với hai mục tiêu: - Tổng quan số bệnh liên quan đến thay đổi nồng độ acid amin dịch sinh học - Tổng quan phương pháp phân