WADA prohibited substances and their biochemical mechanisms

1. WADA prohibited substances and their biochemical mechanisms

2. M3 Gene doping • The following, with the potential to enhance sport performance, are prohibited: • The transfer of polymers of nucleic acids or nucleic acid analogues; 轉殖核酸聚合物或核酸類似物 • DNA, RNA • The use of normal or genetically modified cells. 使用正常或基因改造細胞。

3. Anabolic Androgenic Steroids同化性代謝雄性荷爾蒙

4. Anabolic Androgenic Steroids同化性代謝雄性荷爾蒙 Danazol Gestrinone nandrolone

5. androgen receptor modulators選擇性 雄激素受體 調節劑 andarine BMS-564,929 ostarine

6. Ex Biochem c25-act transcript 25.12 Binding to the Response ElementIs Activated by Ligand-Binding • Binding of ligand to the C-terminal domain increases the affinity of the DNA-binding domain for its specific target site in DNA. Figure 25.19

7. S2 peptide hormonesErythropoietin (EPO) • binding to erythropoietin receptor • highly glycosylated 醣化(40% of total molecular weight) • half-life in blood ~ 5 hr, vary between endogenous and various recombinant 混合versions • Additional glycosylation or other alterations of EPO via recombinant technology have led to the increase of EPO's stability in blood (thus requiring less frequent injections).

8. EPO binds to EpoR on red cell progenitor surface and activates Janus kinase 2 (JAK2) signaling cascade Jak-Stat Pathways. Jak-Stat pathways entail the receptor Janus kinase (Jak) and the signal transducer and activator of transcription (Stat).

9. EPO-related • Methoxy polyethylene glyco-epoetin beta (CERA) 超長效紅血球生成素 • Continuous erythropoietin receptor activator 連續性紅血球生成素受體活化劑 •  strucutre similar to the previous synthetic EPO drugs, except that it is connected to a chemical called polyethylene glycol (PEG), which makes it last 6-10 X longer in the body. • Non-erythropoietic EPO-Receptor agonists • asialo EPO 無唾液酸紅血球生成素

10. Hypoxia-inducible factors (HIF) • Transcription factors • Functions: angiogenesis 血管增生, development, metabolism • HIF Stabilizers 穩定劑 • HIF 活化劑: 氬氣及氙氣 • 氮氣

11. mechanism of HIF

12. Peptide hormones • 人類絨毛膜性腺激素(Chorionic Gonadotrophin, CG), or human CG (hCG) • 黃體化激素 (Luteinizing Hormone, LH) • Both released during pregnancy懷孕 • 也可幫助女性懷孕 • Manny Ramirez • 相關釋放因子 releasing factors

13. CG and LH • stimulate testosterone production • Failed drug test if urinary testosterone to epitestosterone (T/E) > 6. • hCG ↑endogenous production of testosterone and epitestosterone without increasing the urinary T/E ratio above normal • hCG also be used following cessation of prolonged anabolic steroid use • hasten a return to normal testicular function and size, when circulating testosterone very low.

18. 生長激素 growth hormone • 生長激素(GH)及相關釋放因子， 包括生長素釋素(GHRH) • 其他生長因子 • Insulin-like Growth Factor-1 (IGF-l) 似(類)胰島素生長因子

19. 生長激素 growth hormone

20. S3 beta-2 agonists 致效劑 • Beta-2 adrenergic receptor 腎上腺素受體agonists • smooth muscle relaxation 平滑肌舒張(鬆弛) • dilation of bronchial 支氣管 passages通道 • vasodilation in muscle and liver  • Used to treat asthma and other pulmonary disorders. • anabolic effects (↑ muscle mass, ↓body fat percentage and faster recovery rates)? • Most studies showed no ergogenic effect

21. S3 beta-2 agonists 致效劑

22. S4. Hormone and metabolic modulators 荷爾蒙及代謝調節劑 • Aromatase inhibitors芳香環轉化酶抑制劑 Testosterone  estradiol androstenedione estrone

23. S4. Hormone and metabolic modulators 荷爾蒙及代謝調節劑 • Selective estrogen receptor modulators (SERMs) 選擇性雌激素受體調節劑 • anti-estrogenic substances 抗雌激素物質

24. S4. Hormone and metabolic modulators – myostatin inhibitors • Agents modifying myostatin 肌肉生長抑制素 function • myostatin inhibitors 肌肉生長抑制素抑制劑 • Disabled myostatin gene increase muscle size • https://www.youtube.com/watch?v=yw4Ci6UrOK0

25. Ex Biochem c9-genetics Myostatin mutations in animals

26. Ex Biochem c9-genetics

27. 5. Metabolic modulators 代謝調節劑 • 5.1 腺苷單磷酸活化蛋白激酶調節劑 • AMP-activated kinase, AMPK • 例如AICAR • 過氧化體增生劑活化受體delta致效劑 • peroxisome proliferator-activated receptordelta, PPARdelta • 例如 GW 1516

28. Ex Biochem c5-CHO metabolism AMP-activated protein kinase activation

29. Effect of AICAR on AMPK Pokrywka, 2015

31. Pokrywka, 2015

32. Ex Biochem c25-act transcript PPARs pathway

33. Ex Biochem c25-act transcript GW501516, GW1516PPARdelta agonist Cause cancer in rats, development stopped by GSK

34. Effects of GW501516 on PPARdelta Pokrywka, 2015

35. Ex Biochem c25-act transcript WT: wild type TG: transgenic, 基因轉殖 expression of an activated form of PPARdelta in skeletal muscle Wang YX, PLOSB 2004

36. Ex Biochem c25-act transcript GW501516: PPARdelta agonist Wang YX, PLOSB 2004

37. Ex Biochem c25-act transcript GW1516 ↑endurance running performance after 5 weeks of training in mice V: vehicle only, GW: GW1516 Narkar, Cell 2008

38. Ex Biochem c25-act transcript GW1516 in combination with training↑oxidative enzyme expression in mouse quadriceps V: vehicle only, GW: GW1516, Tr: training, Tr+GW: training + GW1516 Narkar, Cell 2008

39. Ex Biochem c25-act transcript Proposed mechanismPGC-1alpha AICAR 5-aminoimidazole-4-carboxamide ribonucleotide Narkar, Cell 2008

40. 粒線體生合成的基因調控機制 Ex Biochem c25-act transcript Reznick et al, 2006

41. 5. Metabolic modulators 代謝調節劑 • 5.2 胰島素 • 5.3 Trimetazidine • 可代謝成amphetamine 安非他命 • 興奮劑

42. Ex Biochem c5-CHO metabolism

43. S5 Diuretics and masking agents利尿劑與干擾劑 • 血漿擴張劑 • 甘油及靜脈注射albumin dextran,hydroxyethylstarch, 甘露醇 mannitol • 利尿劑 • Acetazolamide 一種利尿劑, inhibitor of carbonic anhydrase • HCO3- + H+  H2CO3  H2O + CO2 • In kidney, allowing the reabsorption of HCO3-, sodium, and chloride. By inhibiting this enzyme, these ions are excreted, along with excess water, 

44. S6 Stimulants 興奮劑prohibited in-competition賽內禁用 • Amfetamine (amphetamine): 安非他命 • Cathine去甲偽麻黄鹼；mephedrone甲氧麻黄酮: 可轉換為安非他命 amphetamine Cathine mephedrone

45. S6 Stimulants 興奮劑prohibited in-competition賽內禁用 • Ephedrine 麻黃 • Pseudoephedrine 偽麻黃鹼 • 一種「血管收縮劑」。過敏或感冒(流感)所引起的鼻塞，主要因鼻腔內微血管充血而腫脹的關係。此藥使鼻子內層的血管收縮，使充血腫脹的鼻腔恢復正常，而達到呼吸順暢的目的。可以紓解因為鼻竇腫脹而引起的不舒服﹑疼痛和呼吸不適。 ephedrine pseudoephedrine