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.

去年我们的大部分研究工作都集中在一类阻燃剂——多溴二苯醚 (PBDE) 上。商业上以基于溴含量的混合物形式生产PBDE。例如五大湖DE-71？ (DE-71) 是一种含有 71% 溴的商业混合物，主要用作聚氨酯泡沫中的阻燃剂。 DE-71 含有五溴、四溴和六溴二苯醚。 PBDE 存在于哺乳动物组织和体液中，包括人类脂肪、血清和乳汁。人类样本中最常见的同系物是 BDE-47（四溴二苯醚）、BDE-99 和 BDE-100（均为五溴二苯醚）。这些也是 DE-71 商业混合物中的主要同系物。主要的六溴二苯醚是 BDE-153，虽然与四溴二苯醚和五溴二苯醚同源物相比，它是次要成分，但它具有高度亲脂性，并且在体内可能更持久。 NTP 目前正在设计 DE-71 混合物的生物测定法。 PBDE 的急性毒性相对较低，而且似乎不具有致突变性。然而，PBDE 同系物在结构上与 TCDD 和 PCB 相似，并且被认为具有与这些化学品相同的毒性机制。此外，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控制的途径。 对同系物 BDE-47、-99 和 ?153 的 ADME 研究涵盖了从 0.1 至 1000 umol/kg 的广泛剂量范围。口服玉米油制剂后，14C-BDE-47、-99 和 -153 可以很好地吸收（70% 至 85%）。组织分布在 10,000 倍剂量范围内呈线性，至少对于较大的组织而言是这样。在 B6C3f1 小鼠和 F344 大鼠中研究了 14C 标记的 BDE-47 的代谢和处置。 BDE-47 放射性的组织分布和排泄存在性别和物种差异。雄性小鼠以原形形式以尿液形式排出给药剂量的 30%。一般来说，小鼠的组织积累少于大鼠。代谢研究鉴定出胆汁中的谷胱甘肽结合物。在尿液中鉴定出葡萄糖醛酸和 2,4-二溴苯酚的硫酸盐结合物。这似乎是二苯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。大鼠口服0.1至1000umol/kg剂量后24小时内，约50%的剂量通过粪便排出，其中16%未被吸收。高达 2% 通过尿液排出，34-38% 保留在组织中，主要是脂肪中。小鼠在尿液中的排泄量比大鼠多，在粪便中的排泄量比大鼠少。对大鼠多次给药后观察到组织积聚。在雄性大鼠尿液中鉴定出 BDE-99、2,4,5-三溴苯酚及其葡萄糖醛酸苷的两个二氢羟基-S-谷胱甘肽和两个 S-谷胱甘肽缀合物、两个单羟基化 BDE-99 葡萄糖苷酸和三个单羟基化四溴二苯基苯醚。 BDE-99 比 BDE-47 或 153 经历更广泛的代谢。雄性大鼠吸收的口服剂量的一半在 10 天内排出，大部分作为源自芳烃氧化物代谢的代谢物。在单次和多次剂量以及与放射性标记的 2、 2',4,4'-四溴二苯醚 (BDE47) 和 2,2',4,4',5-五溴二苯醚 (BDE99)。在单次暴露研究中，1-100 µmol/kg 范围内的剂量对雄性大鼠中 BDE153 的分布影响很小或没有影响。没有检测到 BDE153 体内命运的重大性别或物种差异。 BDE153 为：1) 大鼠或小鼠灌胃后约 70% 被吸收。 2）保留在组织中。 3）代谢差，排泄慢。混合物研究表明，相对而言，更多的BDE47分布到脂肪组织，更多的BDE153在肝脏中积累，而BDE99被最大程度地代谢。 BDE153 可能因灌胃后“首过”分布至组织后代谢和消除极少而保留在肝脏中。最近关于胡薄荷酮及其含呋喃代谢物薄荷呋喃毒性的 NTP 研究指出需要或更多有关含呋喃化学物质代谢活化的信息。在代谢方案中，通常假设呋喃中的双键之一被氧化成环氧化物，并且环氧化物发生反应或重排成二氧丁烯（例如，来自呋喃的顺丁烯二醛）。然而，从严格的热力学角度来看，直接形成二氧代丁烯是有利的。对人类肝毒物质 4-ipomeanol 的体外代谢进行了研究，试图了解更多有关呋喃代谢活化的信息。伊波美宁 (IPN)、4-伊波美醇 (4-IPO)、1-伊波美醇和 1,4-伊波美二醇 (DIOL) 是在受霉菌损坏的甘薯中发现的有毒 3-取代呋喃。 IPN 和 4-IPO 毒性最强，但都会产生严重的肺毒性，需要代谢激活。虽然这些呋喃的毒性已得到充分描述，但代谢研究提供的数据有限。大鼠肝微粒体对 4-IPO 代谢的初步研究表明，4-IPO 氧化为 IPN，还原为 DIOL，并且 IPN 比 4-IPO 或 DIOL 更容易代谢为活性物质。 IPN和Gly的温育产生2′-吡咯啉-5′-酮加合物，证实IPN被代谢为内二代谢物。 N-乙酰半胱氨酸与烯二醛的5′-醛反应，得到两个2′，5′-二氢-2′-羟基呋喃，通过2′-OH和3′-酮基之间的氢键稳定。 IPN的内二元代谢物与一种GSH反应产生了几种加合物，包括由GSH 1,2-加成衍生的吡咯和5′-醛，以及由GSH 1,4-加成衍生的两个三环2′-吡咯啉。 4?-位。吡咯和2′-吡咯啉GSH 加合物的身份通过观察来自Cys 与IPN 的内二代谢物缀合的结构相似的加合物而得到证实。单-GSH 和双-GSH 加合物源自在 4-IPO 和 GSH 培养的大鼠肝微粒体中将 GSH 1,2-和 1,4-加成至 4-IPO 的内代谢产物。 4-IPO 孵育中也发生了 4-IPO 依次氧化为 IPN，然后氧化为 enedial 代谢物，然后是 GSH 缀合。观察到的体外代谢物均不需要呋喃环氧化物的中介作用，而一些氮杂环只能由氨基与烯二醛反应产生。