Variations in catechol O-methyltransferase activity in rodent tissues: possible role in estrogen carcinogenicity

Catechol-O-methyltransferase (COMT) EC 2.1.1.6 EC] ] is a ubiquitouscytosolic enzyme which has a pertinent role in the inactivationof both natural and synthetic catechol estrogens in mammaliantissues. We have compared the COMT activity in mouse, hamsterand rat kidney, liver and red blood cells and examined the kineticcharacteristics of this enzyme in the latter two species usingvarious catechol estrogens as substrates. Results presentedhere indicate that the ratios of COMT activity in the kidneyversus the liver of the rat and mouse are nearly identical,0.48–0.52, whereas there is a 29-fold ratio between thelevel of COMT activity in these two tissues in the hamster.In red blood cells, the level of COMT activity is 4- and 12-foldlower in the hamster compared to mouse and rat, respectively.When the kinetic characteristics of this enzyme were assessedin the hamster and rat kidney and liver, except for 2-hydroxymoxestrolwhich had an apparent K_m value of 15–48 µM, theother catechol estrogen substrates exhibited K_m values rangingfrom 1–10 µM. Generally, the V_max values were markedlyhigher in the rat kidney and liver than those observed in correspondinghamster tissues. The significantly lower COMT activity in thehamster liver and red blood cells suggests that under chronicestrogen treatment at high doses, the concentration of catecholestrogens in these tissues may exceed the capacity of COMT toeffectively catalyse their O-methylation into inactive metabolites.The resulting accumulation of catechol estrogens may contributeto the estrogen carcinogenicity observed in the hamster liverand kidney. Additionally, when 2-hydroxy-estrone was used asa substrate, the estrogen-induced renal carcinoma exhibitedonly 8.6% of the COMT activity found in the normal kidney.