Pharmacogenetics of methotrexate in patients with rheumatoid arthritis

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(1)Pharmacogenetics of methotrexate in patients with rheumatoid arthritis Wessels, J.A.M. Citation Wessels, J. A. M. (2007, October 11). Pharmacogenetics of methotrexate in patients with rheumatoid arthritis. Retrieved from https://hdl.handle.net/1887/12436 Version:. Corrected Publisher’s Version. License:. Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded from:. https://hdl.handle.net/1887/12436. Note: To cite this publication please use the final published version (if applicable)..

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(5) HK '.2 IHER@ENM:F:M>L BGAB;BM =BK><MER =BAR=KH?HE:M> K>=N<M:L>" , MARFB=RE:M>LRGMA:L>.-:G=MA> :FBGHBFB=:SHE> <:K;HQ:FB=>. KB;HGN<E>HMB=>#,MK:GL?HKFRE:L> )MA>K?HE:M>>GSRF>LLN<A:LF>MARE>G>M>MK:AR. =KH?HE:M>K>=N<M:L>'." ,F:R;>BGN>G<>=BG=BK><MER B@NK> '.2>GM>KLMA><>EE OB:MA>K>=N<>=?HE:M><:KKB>K, PA>K>:LL>O>K:EFNEMBK>LBLM:G<>IKHM>BGL',*L:G= MA>* @ER<HIKHM>BG* @IIKH;:;ER?:<BEBM:M><>EENE:K>?NQ5 7 MTX. Folic acid RFC1. DHF MTX. Folic acid DHFR. FPGS THF MTXglu AICAR AICART ’ASE. dUMP MTHFR. FAICAR. 5,10-CH2=THF dTMP. 5-CH3-THF homocysteine. TS. methionine. Figure 1. Simplified representation of the folate pathway. Shown are enzymes and metabolites, involved in the folate pathway. MTX inhibits cellular synthesis of purines, pyrimidines and methionine. AICAR = 5aminoimidazole-4-carboxamide-ribonucleotide; AICART’ASE = AICAR transformylase; DHF = dihydrofolate; DHFR = dihydrofolate reductase; dUMP = deoxy-uridine monophosphate; dTMP = deoxy-thymidine monophosphate; FAICAR= formyl-AICAR; FPGS = folylpolyglutamate synthetase; MTHFR = methylene tetrahydrofolate reductase; 5-CH3-THF = 5-methyl tetrahydrofolate; 5,10-CH2=THF = 5,10-methylene tetrahydrofolate; MTX = methotrexate; MTXglu = methotrexate polyglutamate; RFC1 = reduced folate carrier; THF = tetrahydrofolate; TS = thymidylate synthetase. Reproduced, with permission from ref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(10) !<>EELP:LL>>G. FAICAR. MTX ATIC. AICAR. MTXglu. spermine. ATIC. ornithine IMP. AMP. spermidine. ODC. AMPD ’5-NT. putrescine. ’5-NT. adenosine. inosine. SAH. SAM. ADA. homocysteine. methionine MTR MTRR. Figure 2. Simplified representation of the adenosine metabolism and polyamine production pathway. Shown are enzymes and metabolites, involved in the stepwise release of adenosine and in the production of polyamines spermine and spermidine. ADA = adenosine deaminase; AICAR = 5-aminoimidazole-4-carboxamide-ribonucleotide; AMP = adenosine-monophosphate; AMPD = AMP-deaminase; ATIC = 5-aminoimidazole4-carboxamide-ribonucleotide transformylase; FAICAR = formyl-AICAR; IMP = inosine-monophosphate; MTR = methionine synthase; MTRR = methionine synthase reductase; MTX = methotrexate; MTXglu = methotrexate polyglutamate; 5’-NT = 5’-nucleotidase; ODC = ornithine decarboxylase; SAH = S-adenosylhomocysteine; SAM = S-adenosylmethionine. .

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