Reactions of Methotrexate with Hypobromous Acid and Hypochlorous Acid

• Published in: Chemical & pharmaceutical bulletin Vol. 67; no. 11; pp. 1250 - 1254
• Main Authors: Suzuki, Toshinori, Takeuchi, Rie
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.11.2019; Pharmaceutical Soc Japan; Japan Science and Technology Agency
• Subjects: 3′-bromomethotrexate; 3′-chloromethotrexate; Amino acids; Arthritis; Bromates - chemistry; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Cytotoxicity; Eosinophils; Folic acid; Humans; hypobromous acid; Hypochlorous acid; Hypochlorous Acid - chemistry; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Life Sciences & Biomedicine; Methotrexate; Methotrexate - chemistry; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Rheumatoid arthritis; Science & Technology; Taurine; hypobromous acid; MYELOPEROXIDASE; hypochlorous acid; EFFICACY; 3 '-chloromethotrexate; DISEASE; methotrexate; BROMIDE; EOSINOPHIL PEROXIDASE; DERIVATIVES; 3 '-bromomethotrexate; LEUKOCYTE; 3′-chloromethotrexate; 3′-bromomethotrexate
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c19-00602

Methotrexate is a folate antagonist cytotoxic drug employed in the therapy of cancers and rheumatoid arthritis. Hypobromous acid (HOBr) and hypochlorous acid (HOCl) are generated by eosinophils and neutrophils at inflammation sites. The administered methotrexate may encounter HOBr and HOCl, and react with them to generate products. When methotrexate was incubated with HOBr or HOCl at pH 7.4 and 37°C for 30 min, a single product was generated almost exclusively in each case, identified as 3′-bromomethotrexate for HOBr and 3′-chloromethotrexate for HOCl. When methotrexate was incubated with HOCl in the presence of NaBr, the concentration of 3′-bromomethotrexate increased with decreasing concentration of 3′-chloromethotrexate in a dose-dependent manner with NaBr, probably due to the formation of HOBr. Free amino acids suppressed the reactions of methotrexate with HOBr and HOCl. Taurine suppressed the HOCl reaction but not the HOBr reaction. These results suggest that 3′-bromomethotrexate and 3′-chloromethotrexate may be generated from methotrexate at inflammation sites in humans, although their formation will be suppressed by coexistent amino acids.