首页> 外文期刊>Aquatic Toxicology >Slow O-demethylation of methyl triclosan to triclosan, which is rapidly glucuronidated and sulfonated in channel catfish liver and intestine.
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Slow O-demethylation of methyl triclosan to triclosan, which is rapidly glucuronidated and sulfonated in channel catfish liver and intestine.

机译:甲基三氯生缓慢地O-去甲基化为三氯生,三氯生在沟cat鱼的肝脏和肠道中迅速被葡萄糖醛酸化和磺化。

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The antibacterial personal care product triclosan is discharged in municipal waste, and converted in part by bacteria in sewage sludge and soil to its more lipid-soluble methyl ether, methyl triclosan. Triclosan and methyl triclosan have been detected in water, sediment, fish and invertebrates near sewage treatment facilities. Understanding the biotransformation of methyl triclosan and triclosan in a model food fish, the channel catfish, will be of value in assessing the likelihood that these compounds will bioaccumulate in exposed fish, and therefore potentially pass up the food chain. We hypothesize that cytochrome P450 will catalyze the O-demethylation of methyl triclosan to yield triclosan, which is likely to undergo glucuronidation or sulfonation of the phenolic hydroxyl group. Conversion of methyl triclosan to triclosan was measured by LC/MS/MS following aerobic incubation of varying concentrations of methyl triclosan with NADPH and hepatic and intestinal microsomes from untreated, 3-methylcholanthrene-treated (10 mg/kg, i.p.) or PCB-126-treated (0.1 mg/kg, i.p.) channel catfish (n=4 per treatment group). The Km values for methyl triclosan were similar for untreated, 3-methylcholanthrene-treated and PCB-126-treated catfish liver microsomes, ranging from 80 to 250 micro M. Vmax values for O-demethylation ranged from 30 to 150 pmol/min/mg protein, with no significant differences between controls, PCB-126-treated or 3-methylcholanthrene-treated fish, suggesting that methyl triclosan O-demethylation was not a CYP1-catalyzed reaction. Methyl triclosan O-demethylation activities in intestinal microsomes were similar to or lower than those found with liver microsomes. The calculated rate of O-demethylation of methyl triclosan in catfish liver at 1 micro M, a concentration reported in exposed fish, and 21 degrees C, an early summer water temperature, is 0.10 pmol/min/mg protein. This slow rate of metabolism suggests that upon continued exposure, methyl triclosan may bioaccumulate in the channel catfish. Triclosan itself, however, was readily glucuronidated by hepatic and intestinal microsomes and sulfonated by hepatic and intestinal cytosol. Triclosan glucuronidation followed Michaelis-Menten kinetics when rates were measured across a concentration range of 5-1000 micro M, whereas triclosan sulfonation exhibited substrate inhibition at concentrations above 10-20 micro M in both intestinal and hepatic cytosol. Based on the enzyme kinetic constants measured in hepatic and intestinal fractions at 21 degrees C, triclosan at 1 micro M could be glucuronidated at rates of 23 and 3.2 pmol/min/mg protein respectively in liver and intestine, and sulfonated at rates of 277 (liver) and 938 (intestine) pmol/min/mg protein. These rates are much higher than the rates of demethylation of methyl triclosan, and suggest that triclosan would be rapidly cleared and unlikely to bioaccumulate in catfish tissues.
机译:抗菌个人护理产品三氯生排放到城市垃圾中,并部分地由污水污泥和土壤中的细菌转化为脂溶性更强的甲醚甲基三氯生。在污水处理设施附近的水,沉积物,鱼类和无脊椎动物中检测到三氯生和甲基三氯生。了解模型食用鱼(channel鱼)中甲基三氯生和三氯生的生物转化,对于评估这些化合物在裸露的鱼中生物蓄积并因此可能通过食物链的可能性非常有价值。我们假设细胞色素P450将催化三氯生的O-去甲基化以产生三氯生,三氯生可能经历酚醛酸的葡萄糖醛酸化或磺化。在将不同浓度的三氯生与NADPH以及来自未处理的,3-甲基胆固醇处理过的(10 mg / kg,ip)或肝-肠微粒体的不同浓度的三氯生进行好氧孵育后,通过LC / MS / MS测定了三氯生向三氯生的转化-处理(0.1 mg / kg,腹膜内)的cat鱼(每个处理组n = 4)。未经处理的,3-甲基胆固醇处理的和PCB-126处理的cat鱼肝微粒体的甲基三氯生的K m 值相似,范围为80至250 microM。V max O-去甲基化的值范围为30至150 pmol / min / mg蛋白质,在对照组,PCB-126处理或3-甲基胆固醇处理的鱼之间没有显着差异,表明甲基三氯生O-去甲基化不是CYP1催化反应。肠道微粒体中的甲基三氯生O-去甲基活性与肝脏微粒体中的相似或更低。 micro鱼肝脏中甲基三氯生的O-去甲基化率(在裸鱼中报道的浓度)为1 micro M时,在初夏水温为21摄氏度时,为0.10 pmol / min / mg蛋白质。这种缓慢的新陈代谢速度表明,持续暴露后,三氯生甲基可能在channel鱼中生物蓄积。然而,三氯生本身很容易被肝和肠微粒体葡萄糖醛酸化,并被肝和肠细胞质溶胶磺化。当在5-1000 micro M的浓度范围内测量速率时,三氯生葡萄糖醛酸化遵循Michaelis-Menten动力学,而三氯生磺化在肠道和肝细胞溶质中均在高于10-20 micro M的浓度下显示底物抑制作用。根据在21°C的肝和肠部分中测得的酶动力学常数,可以在肝脏和肠中分别以23和3.2 pmol / min / mg的葡萄糖苷酸速率对1 micro M的三氯生进行葡萄糖醛酸化,并在277的速率下进行磺化(肝)和938(肠)pmol / min / mg蛋白。这些速率远高于三氯生甲基的去甲基化速率,表明三氯生会迅速清除,并且不太可能在cat鱼组织中生物蓄积。

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