期刊
PHARMACOGENETICS
卷 12, 期 7, 页码 517-528出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00008571-200210000-00003
关键词
kinetics; catechol-O-methyltransferase polymorphism; estrogen
资金
- NCI NIH HHS [CA77550] Funding Source: Medline
- NIEHS NIH HHS [P30 ES03819, ES07141] Funding Source: Medline
The major detoxification pathway of the carcinogenic catechol estrogens is methylation by catechol-O-methyltransferase (COMT). It has been hypothesized that the enzyme encoded by the low-activity allele (COMTL) has a lower catalytic activity for catechol estrogen methylation than that encoded by the high activity allele (COMTH). We expressed and purified human soluble (S)COMTH and S-COMTL in Escherichia coli and characterized the methylation of 2- and 4-hydroxyestradiol (2- and 4-OH-E2). There were no differences between the kinetic parameters for COMTH and COMTL. The kinetic parameters for S-adenosylmethionine (SAM), the methyl donor in these reactions, also did not differ for COMTH and COMT1. S-adenosylhomocysteine, the demethylated SAM metabolite, inhibited methylation of the catechol estrogens in a non-competitive manner similarly for COMTH and COMT1. Each COMT substrate tested inhibited the methylation of other substrates in a mixed competitive and non-competitive fashion similarly for COMTH and COMT1. Furthermore, in cytosolic fractions of COMTHH (MCF-10A and ZR-75-1) and COMTLL (MCF-7 and T47D) human breast epithelial cell lines, no differences were detected between the kinetic parameters of COMT with respect to 2-and 4-OH-E2 methylation; nor were COMT protein levels associated with the COMT genotype. These data suggest that the decreased COMT enzymatic activity that has been detected in human tissue in association with the COMTL allele is not reflected by differences in the affinity or capacity of COMTH and COMTL for catechol estrogen methylation. These results raise the question of what accounts for the difference in COMT activity associated with the COMTHH and COMTLL genotypes in human tissue.
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