Methotrexate pharmacogenetics

Keywords Azathioprine methotrexate pharmacogenetics polymorphisms rhen-matoid arthritis sulfasalazine tumor necrosis factor antagonists. 

Ranganathan P, Mcleod HL (2006) Methotrexate pharmacogenetics first step toward individualized therapy in rheumatoid arthritis. Arthritis Rheum 54(5) 1366-1377... 

Ulrich, C.M., et al., "Pharmacogenetics of Methotrexate Toxicity Among Marrow Transplantation Patients Varies with the Methylenetetrahydrofolate Reductase C677T Polymorphism," Blood, 98, 231-234 (2001). 

A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination. Pharmacogenet Genomics, 15, 277—285. 

This chapter highlights some of the recent major pubhcations in the field of pharmacogenomics in RA and describes the implications of this field for future research and cUnical care. The pharmacogenetics of three major DMARDs (methotrexate [MTX], azathioprine [AZA], and sulfasalazine [SSZ]) and one class of biologic DMARDs, the tumor necrosis factor (TNF) antagonists, in RA, are reviewed. 

Fig. 14.1 Cellular pathway of methotrexate. ABCBl, ABCCl-4, ABC transporters ADA, adenosine deaminase ADP, adenosine diphosphate AICAR, aminoimidazole carboxamide ribonucleotide AMP, adenosine monophosphate ATIC, AICAR transformylase ATP, adenosine triphosphate SjlO-CH -THF, 5,10-methylene tetrahydrofolate 5-CHj-THF, 5-methyl tetrahydro-folate DHFR, dihydrofolate reductase dTMP, deoxythymidine monophosphate dUMP, deoxy-uridine monophosphate FAICAR, 10-formyl AICAR FH, dihydrofolate FPGS, folylpolyglutamyl synthase GGH, y-glutamyl hydrolase IMP, inosine monophosphate MTHFR, methylene tetrahydrofolate reductase MTR, methyl tetrahydrofolate reductase MTX-PG, methotrexate polyglutamate RFCl, reduced folate carrier 1 TYMS, thymidylate synthase. Italicized genes have been targets of pharmacogenetic analyses in studies published so far. (Reproduced from ref. 73 by permission of John Wiley and Sons Inc.)...

Urano, W., Taniguchi, A., Yamanaka, H., et al. (2002) Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenetics. 12, 183-190. 

Ulrich CM, Yasui Y, Storb R et al. Pharmacogenetics of methotrexate toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001 98 231-234. 

Key Words Acute lymphoblastic leukemia pharmacogenetics single nucleotide polymorphisms outcome English folate pathway methotrexate... 

Key words Pharmacogenetics, Polymorphisms, Rheumatoid, Arthritis, Methotrexate, Azathioprine,... 

Dervieux T, Kremer J, Lein DO, Capps R, Barham R, Meyer G, Smith K et al (2004) Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis. Pharmacogenetics 14 733-739... 

Becker ML, Leeder JS (2010) Developmental pharmacogenetics in pediatric rheumatology utilizing new paradigm to efficiently treat patients with juvenile idiopathic arthritis with methotrexate. Hum Genomics Proteomics 2010 257120... 

Pharmacogenetics may influence the response to antifolates and their toxicity. A mutation in methylenetetrahydrofolate reductase, the enzyme that generates methylenetetrahydrofolate cofactor for TS, reduces its activity and thereby increases methotrexate toxicity. The presence of this polymorphism in leukemic cells confers increased sensitivity to methotrexate, and may also modulate the toxicity and therapeutic effect of pemetrexed, a predominant TS inhibitor. Likewise, polymorphisms in the promoter region of TS affect its expression, and by altering the intracellular levels ofTS, modulate the response and toxicity of both antifolates and fluoropyrimidines. 

Hulot J S, Villard E, Maguy A, et al. (2005). A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination. Pharmacogenet. Genomics. 15 277-285. 

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