Xenobiotic Metabolism

异生物质代谢

• 批准号: 7327227
• 负责人: Leo T Burka
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7327227
• 关键词: Xenobiotic; Metabolism

The majority of our research effort in the past year has been on a class of flame retardants, polybrominated diphenyl ethers (PBDE). PBDE?s are produced commercially as mixtures based on bromine content. For instance, Great Lakes DE-71? (DE-71) is a commercial mixture containing 71% bromine used primarily as a flame retardant in polyurethane foams. DE-71 contains penta-, tetra- , and hexa-brominated diphenyl ethers. PBDE?s are found in mammalian tissues and fluids, including human adipose, serum, and milk. The most prevalent congeners in human samples are BDE-47 (a tetraBDE), BDE-99, and BDE-100 (both pentaBDE?s). These are also the main congeners in the DE-71 commercial mixture. The major hexaBDE is BDE-153 and while it is a minor component compared to the tetra- and penta-congeners, it is highly lipophilic and may be more persistent in vivo. The NTP is currently designing a bioassays for the DE-71 mixture. PBDE?s have relatively low acute toxicity and appear to be non-mutagenic. However, PBDE congeners are structurally similar to TCDD and PCB?s and have been considered to have mechanisms of toxicity in common with those chemicals. Additionally, BDE-47 and its hydroxylated metabolites are structurally similarity to thyroxin and may interfere with thyroid hormone controlled pathways. ADME studies of the congeners, BDE-47, -99, and ?153 have covered a wide range of doses from 0.1 to 1000 umol/kg. 14C-BDE-47, -99 and -153 are well absorbed (70 to 85%) from oral administration of a corn oil formulation. Tissue distribution is linear over the 10,000-fold range of doses, at least for the larger tissues. The metabolism and disposition of 14C-labeled BDE-47 was studied in B6C3f1 mice and F344 rats. Sex and species differences were observed in tissue distribution and excretion of BDE-47 derived radioactivity. Male mice excreted up to 30% of the administered dose in urine unchanged. In general, tissue accumulation was less in mice than rats. Metabolism studies identified gluthathione conjugates in bile. A glucuronide and a sulfate conjugate of 2,4-dibromophenol were identified in urine. This appears to be the first report of metabolic cleavage of a diphenyl ether. The metabolism and disposition of 14C-labeled BDE-99 was studied on F344 rats and B6C3 F1 mice. Within 24 hr following oral doses ranging from 0.1 to 1000 umol/kg to rats, about 50% of the dose was excreted in feces, this includes 16% unabsorbed. Up to 2% was excreted in urine and 34-38% remained in tissues, mostly in fat. Mice excreted more in urine and less in feces than rats. Tissue accumulation was observed following multiple dosing to rats. Two dihydrohydroxy-S-glutathionyl and two S-glutathionyl conjugates of BDE-99, 2,4,5-tribromophenol and its glucuronide, two monoydroxylated BDE-99 glucuronides and three monohyroxylated tetrabromodiphenyl phenyl ether were identified in male rat urine. BDE-99 undergoes more extensive metabolism than BDE-47 or 153. Half of the absorbed oral dose in male rats was excreted in 10 days mostly as metabolites derived from arene oxide metabolism. The disposition of the 14C-labeled polybrominated diphenyl ether (PBDE), 2,2', 4,4',5,5'-hexaBDE (BDE153) was investigated in rodents following single and multiple doses and in a mixture with radiolabeled 2,2',4,4'-tetraBDE (BDE47) and 2,2',4,4',5-pentaBDE (BDE99). In single exposure studies, there was little or no effect of dose on BDE153 disposition in male rats in the range of 1-100 ?mol/kg. No major sex or species differences in the in vivo fate of BDE153 were detected. BDE153 was: 1) approximately 70% absorbed in rats or mice following gavage. 2) retained in tissues. 3) poorly metabolized and slowly excreted. Mixture studies indicated that, relative to each other, more BDE47 was distributed to adipose tissue, more BDE153 accumulated in liver, and BDE99 was metabolized to the greatest extent. BDE153 was probably retained in liver due to minimal metabolism and elimination after "first pass" distribution to the tissue following gavage. Recent NTP studies on the toxicity of pulegone and its furan-containing metabolite menthofuran pointed out the need or more information on the metabolic activation of furan-containing chemicals. In metabolic schemes, it is generally assumed that one of the double bonds in furan is oxidized to an epoxide and the epoxide either reacts or undergoes a rearrangement to a dioxobutene (for example, cis-butenedial from furan). However, formation of the dioxobutene directly would be favored on strictly thermodynamic grounds. The in vitro metabolism of 4-ipomeanol, a human hepatotoxicant, has been investigated in an attempt learn more about metabolic activation of furans. Ipomeanine (IPN), 4-ipomeanol (4-IPO), 1-ipomeanol, and 1,4-ipomeadiol (DIOL) are toxic 3-substituted furans found in mold-damaged sweet potatoes. IPN and 4-IPO are the most toxic, but all produce severe pulmonary toxicity requiring metabolic activation. While the toxicity of these furans is well described, metabolism studies have provided limited data. Initial studies of 4-IPO metabolism by rat liver microsomes demonstrated oxidation of 4-IPO to IPN and reduction to DIOL and that IPN was more easily metabolized to a reactive species than 4-IPO or DIOL. Incubation of IPN and Gly produced a 2?-pyrrolin-5?-one adduct establishing that IPN was metabolized to an enedial metabolite. N-Acetylcysteine reacted with the 5?-aldehyde of the enedial to give two 2?,5?-dihydro-2?-hydroxyfurans stabilized by H-bonding between the 2?-OH and 3?-keto groups. Reaction of the enedial metabolite of IPN with one GSH gave several adducts including a pyrrole derived from 1,2-addition of GSH to the 5?-aldehyde as well as two tricyclic 2?-pyrrolines derived from 1,4-addition of GSH at the 4?-position. The identities of pyrrole and 2?-pyrroline GSH adducts were confirmed by observation of structurally similar adducts from Cys conjugation with the enedial metabolite of IPN. Mono-GSH and bis-GSH adducts were derived from both 1,2-and 1,4-addition of GSH to the enedial metabolite of 4-IPO in rat liver microsomal incubations of 4-IPO and GSH. Sequential oxidation of 4-IPO to IPN then to the enedial metabolite followed by GSH conjugation also occurred in the 4-IPO incubations. None of the observed in vitro metabolites, require the intermediacy of a furan epoxide, while several nitrogen heterocycles can only arise from an amino group reacting with the enedial.

过去一年中，我们的大部分研究工作都是在一类阻燃剂，多溴二苯基醚（PBDE）上进行的。 PBDE是基于溴含量的混合物而商业生产的。例如，大湖DE-71？ （DE-71）是一种包含71％溴的商业混合物，主要用作聚氨酯泡沫中的阻燃剂。 DE-71含有五苯基和六溴溴苯基乙烯基醚。 PBDE在哺乳动物组织和液体中发现，包括人脂肪，血清和牛奶。人类样品中最普遍的同类物是BDE-47（A Tetrabde），BDE-99和BDE-100（均为pentabde？s）。这些也是DE-71商业混合物中的主要同源物。主要的Hexabde是BDE-153，虽然它是次要组成部分，而与四型和五角核者相比，它具有高度亲脂性，并且在体内可能更持久。 NTP目前正在为DE-71混合物设计生物测定。 PBDE的急性毒性相对较低，似乎是非毒素的。但是，PBDE同源物在结构上与TCDD和PCB相似，并且被认为具有与这些化学物质的共同毒性机制。另外，BDE-47及其羟基化代谢物在结构上与甲状腺素相似，可能会干扰甲状腺激素受控的途径。 对同类物的ADME研究，BDE -47，-99和？153涵盖了从0.1至1000 Umol/kg的广泛剂量。 14C -BDE -47，-99和-153被口服玉米油配方的吸收（70％至85％）。组织分布在10,000倍的剂量范围内是线性的，至少对于较大的组织。在B6C3F1小鼠和F344大鼠中研究了14C标记的BDE-47的代谢和处置。在BDE-47衍生放射性的组织分布和排泄中观察到性别和物种差异。雄性小鼠在尿液中排出了高达30％的尿液剂量。通常，小鼠的组织积累少于大鼠。代谢研究确定了胆汁中的Gluthathione结合物。在尿液中鉴定出葡萄糖醛酸苷和硫酸盐偶联物为2,4-纤维烯醇。这似乎是二苯基醚代谢裂解的第一份报告。在F344大鼠和B6C3 F1小鼠上研究了14C标记的BDE-99的代谢和处置。口服剂量为0.1至1000 Umol/kg的24小时内，大约50％的剂量被粪便排泄，其中包括16％的未吸收。在尿液中排出多达2％的人，在组织中保留34-38％，主要是脂肪。小鼠在尿液中排出更多，粪便比大鼠更少。多种剂量对大鼠多种剂量后观察到组织的积累。 BDE-99，2,4,5-三溴苯酚及其葡萄糖醛酸苷，两种单羟基化的BDE-99 BDE-99葡萄糖酮，两种二羟基-S-甲基二硫代和两个S-甲基二硫代偶联物，2,4,5-三纤维酚​​及其葡萄糖醛酸烯化剂和三个单氢羟基二羟基化的四氢二羟基二甲基苯基苯基苯基苯基苯基酯均应鉴定。 BDE-99经历了比BDE-47或153更广泛的代谢。雄性大鼠的一半被吸收的口服剂量在10天内被排出，主要是源自氧化物代谢的代谢物。在单剂和多剂量的啮齿动物中研究了14C标记的多溴苯基（PBDE），2,2'，4,4'，4,4'，5,5'-HEXABDE（BDE153）（BDE153），在单剂和多剂量和多剂量的啮齿动物中进行了多种剂量和多剂量的啮齿动物，并在具有放射性2,2'，4,4'tetrabde（bdeTrabde（bdebde）的混合物中，以及4,4'tetrabde（bdeTerabde（bde153））和2-47）和2-2,47，bdebtebde（bde153）和2,2,2,2,2,2,2,2,2,2,2; （BDE99）。在单一暴露研究中，剂量对1-100摩尔/kg范围内雄性大鼠的BDE153处置几乎没有影响。未检测到BDE153的体内命运中的主要性别或物种差异。 BDE153是：1）大鼠在大鼠或小鼠中吸收的大约70％。 2）保留在组织中。 3）代谢不佳，缓慢排泄。混合研究表明，相对于彼此，将更多的BDE47分布到脂肪组织中，在肝脏中积累了更多的BDE153，并且BDE99在最大程度上被代谢。 BDE153可能由于新代谢和消除在“第一次过去”分布后，可能保留在肝脏中。 NTP最近关于pulegone及其含Furan代谢产物的毒性的毒性的研究指出，有关含Furan化学物质的代谢激活的需求或更多信息。在代谢方案中，通常假定Furan中的双键中的一种被氧化为环氧，并且环氧反应或对二氧化烷的重排反应或经历重排（例如，来自Furan的顺式二核）。然而，直接在严格的热力学基础上直接偏爱二恶英。在尝试更多地了解Furans的代谢激活的尝试中，已经研究了4- ipomeanol的体外代谢。 ipomeanine（IPN），4-二氨基酚（4-ipo），1- ipomeanol和1,4- ipomeadiol（diol）是在霉菌损坏的地瓜中发现的有毒的3-取代的Furans。 IPN和4-IPO是最毒性的，但所有IPO都会产生严重的肺毒性，需要代谢激活。尽管这些呋喃的毒性得到了很好的描述，但代谢研究提供了有限的数据。大鼠肝微粒体对4-IPO代谢的初步研究表明，4-IPO至IPN并还原至Diol，并且比4-IPO或DIOL更容易地将IPN代谢为反应性物种。 IPN和Gly的孵育产生了2？-Pyrrolin-5？ - 一种加合物，确定IPN被代谢为启动代谢物。 n-乙酰半胱氨酸与递增的5？醛反应，给出两个2？，5？dihydro-2？-dihydro-2？-hydroxyfurans，通过2？-OH和3？酮基之间的H键稳定稳定。 IPN代谢物与一个GSH的反应给出了几种加合物，包括源自1,2个gsh的吡咯并产生了5？醛的1,2-醛以及两个三环2？ - 吡咯，源自4？点的GSH的1,4--吡咯。通过观察到IPN的Endial代谢物中Cys结合的结构相似加合物，证实了吡咯和2个？ - 吡咯蛋白GSH加合物的身份。 Mono-GSH和BIS-GSH加合物均来自1,2和1,4-在4-IPO和GSH的大鼠肝脏微粒体孵育中的1,2和1,4添加到4-IPO的启动代谢产物中。在4-IPO孵育中，也发生了将4-IPO与IPN的顺序氧化，然后再氧化代谢产物，然后进行GSH结合。观察到的体外代谢产物都不需要呋喃的环氧化物中的中间，而几个氮杂环只能由与eNedial反应的氨基群产生。