Phenolphthalein (PT), used in over-the-counter laxatives, was recently been identified as a multisite carcinogen in rodents, but the molecular species responsible for the carcinogenicity is not known. A catechol metabolite of PT, hydroxyphenolphthalein (PT-CAT), was recently reported and may be the molecular species responsible for at least part of the toxicity/carcinogenicity of PT. For example, formation of free radicals as a result of redox cycling of PT-CAT semiquinone with the quinone present a potential carcinogenesis mechanism. However, the catechol structure also makes PT-CAT a potential substrate of the ubiquitous enzyme catechol-O-methyltransferase (COMT), which inactivates potentially reactive catechol metabolites of a number of molecules, including those of the hormone estradiol. We hypothesized that PT-CAT may inhibit the enzyme catechol-O-methyltransferase (COMT) and therefore potentiate genotoxicity by either PT-CAT itself or the endogenous catechol estrogens (CEs) in susceptible tissues. Studies were conducted to determine the effects of PT treatment and PT-CAT itself on the COMT-mediated catabolism of 4- and 2-hydroxyestradiol both in vitro and in vivo. Female mice were treated with PT (50 mg/kg/d) for 21 days and then sacrificed. PT-CAT concentration in urine plateaus by 7 days of exposure. In vitro experiments demonstrated that PT treatment resulted in an increase in free CEs, which are normally cleared by COMT and a concurrent decrease in the capacity of hepatic catechol clearance by COMT. In vitro, PT-CAT was a substrate of COMT, with kinetic properties within the range measured with endogenous substrates. PT-CAT was an extremely potent mixed-type inhibitor of the O-methylation of the catechol estrogens, with 90-300 nM IC50s. The above data, when taken together, suggest that chronic administration of PT may enhance metabolic redox cycling of both PT-CAT and the catechol estrogens and this, in turn, may contribute to PT-induced tumorigenesis.3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is a potent mutagen formed as a by-product of chlorination of drinking water, particularly where the water contains humic matter. MX has been estimated to account for 50% of the mutagenic activity in some drinking water. A recent bioassay in rats demonstrated an increased tumor incidence, primarily in liver and thyroid. An NTP study in mice is underway to complement the rat study. A distribution/metabolism study of MX in mice is being conducted in support of this study. MX is rapidly absorbed in mice when administered orally and is excreted in urine and feces as several polar metabolites. Tissue/blood ratios are highest inforestomach (>100), glandular stomach, intestine, and kidney, in that order. Intravenous administration results in high, prolonged levels of radioactivity in blood compared to oral dosing. MX disposition appears to be dominated by its chemical reactivity with highest concentrations of radioactivity being found at the site of administration. - F344 rats, B6C3f1 mice, xenobiotic metabolism, Phenolphthalein, MX
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