Xenobiotic Effects on COMT

A xenobiotic is a foreign chemical substance found within an organism that is not normally, naturally produced by or expected to be present within that organism. It can also cover substances which are present in much higher concentrations than are usual.41_SchemaRTS_Eng

  • In humans, 2-Oh and 4-Ohestradiol (catechol estrogens) are rapidly O-methylated to form monomethyl ethers catalyzed by COMT and S-adenosyl-L-methionine.

  • Xenobiotics may strongly inhibit COMT-mediated
    O-methylation of catechol estrogens by xenobiotics and may facilitate the development of estrogen-induced tumors.

  • Xenobiotics may therefore deplete intermediates in the Folate cycle.  Environmental burden of Xenobiotics may create a higher need for methylation support.

Catechol-O-methyl_transferase_baucom-instituteAbstract: COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk - Goodman JE, Lavigne JA, Wu K, Helzlsouer KJ, Strickland PT, Selhub J, Yager JD; Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA.

  • Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol estrogens (CEs), using S-adenosylmethionine (SAM) as a methyl donor.

  • Several studies have indicated that the val108met COMT polymorphism, which results in a 3-4-fold decrease in activity, is associated with increased breast cancer risk.

  • Folate, whose intake levels have also been associated with breast cancer risk, and other micronutrients in the folate metabolic pathway influence levels of SAM and S-adenosylhomocysteine (SAH), a COMT inhibitor generated by the demethylation of SAM.

  • Because these micronutrients have been shown to alter SAM and SAH levels, we hypothesized that they could also affect COMT-catalyzed CE methylation.

  • Although measurements of SAM and SAH were not initially collected, a secondary analysis of data from two nested case-control studies was performed to examine whether serum levels of folate, vitamin B12 (B12), pyridoxal 5′-phosphate (PLP), cysteine and homocysteine, in conjunction with COMT genotype, were associated with breast cancer risk. COMT(HH) (high activity COMT homozygote) breast cancer cases had statistically significantly lower levels of homocysteine (P = 0.05) and cysteine (P = 0.04) and higher levels of PLP (P = 0.02) than COMT(HH) controls. In contrast, COMT(LL) (low activity COMT homozygote) cases had higher levels of homocysteine than COMT(LL) controls (P = 0.05).

  • No associations were seen between B12, COMT genotype, and breast cancer risk. An increasing number of COMT(L) alleles was significantly associated with increased breast cancer risk in women with below median levels of folate (P(trend) = 0.05) or above median levels of homocysteine (P(trend) = 0.02). These findings are consistent with a role for certain folate pathway micronutrients in mediating the association between COMT genotype and breast cancer risk.

These findings are consistent with a role for certain folate pathway micronutrients in mediating the association between COMT genotype and breast cancer risk.