Abstract
The immunosuppressive drug 6-mercaptopurine (6-MP) and its prodrug azathioprine are used in the treatment of inflammatory bowel disease and other disorders of immune regulation (1). Thiopurine methyltransferase (TPMT) inactivates 6-MP by methylation. The genetic variants TPMT *2 to *19 are associated with decreased TPMT activity (2), and TPMT*3A , * 3C , and *2 are the most common deficiency-associated variants (1). A heterozygous TPMT genotype (1 in 10 individuals from the general population) is associated with an increased risk of myelosuppression with standard-dose azathioprine therapy (3) and a favorable response to reduced-dose thiopurine therapy (1). Patients with complete TPMT deficiency (1 in 300 individuals from the general population) are at high risk for myelosuppression (4). The erythrocyte TPMT activity distribution is continuous, and concordance between genotype and phenotype in the carrier range varies, depending on where the cutoff is established between the ranges for carriers and noncarriers. We propose that genetic variation in folate metabolism influences TPMT activity and contributes to the lack of concordance between genotype and phenotype in the carrier range. TPMT irreversibly transfers a methyl group from S -adenosylmethionine (SAM) to 6-MP, forming 6-methylmercaptopurine (6-MeMP) and S -adenosylhomocysteine (SAH). The adenosyl moiety of SAH is subsequently cleaved, and homocysteine is remethylated to methionine. The methyl donor for this folate-dependent remethylation cycle is 5-methyltetrahydrofolate, which is formed from 5,10-methylenetetrahydrofolate (MTHF) in a reaction catalyzed by 5,10-MTHF reductase (MTHFR). The MTHFR 677C>T (A222V) thermolabile variant (5) and the 1298A>C (E429A) variant (6) are associated with decreased MTHFR activity. The homozygous MTHFR 677TT genotype occurs in 8%–10% of the population (7), shows 30%–50% of wild-type activity in lymphocytes (8)(9), and is associated with hyperhomocysteinemia (10), DNA hypomethylation (11), increased risk of neural tube defects(12), and decreased risk of some cancers (13)(14). The homozygous 1298CC …
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.