MECHANISTIC STUDIES ON 1,3-BUTADIENE AND RELATED EPOXIDE-FORMING CHEMICALS
1,3-丁二烯及相关环氧化物形成化学品的机理研究
基本信息
- 批准号:6432435
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Summary of Work: Inhalation carcinogenicity studies on two structural analogues of 1,3-butadiene, isoprene (2-methyl-1,3-butadiene) and chloroprene (2-chloro-1,3-butadiene), demonstrated multiple-organ carcinogenic effects including several sites that were targets of 1,3-butadiene carcinogenicity. Multiple research approaches have been taken to understand and quantify the effects of epoxide-forming chemicals that contribute to the carcinogenicity of this family of chemicals. Analyses of genetic alterations in ras protooncogenes in neoplasms induced by these chemicals revealed a predominance of A to T transversions at K-ras codon 61. To account for over-predictions of circulating epoxybutene concentrations after nose-only inhalation exposure to butadiene, our earlier toxicokinetic model of butadiene disposition was modified to describe enhanced accessibility of endoplasmic reticulum-bound epoxide intermediates to epoxide hydrolase (privileged access) due to the formation of a transient complex between that enzyme and cytochrome P450. In this model, bound epoxide P450 products are hydrolyzed in competition with release of the epoxides into the cytosol. The model was extended to include hydrolysis and/or glutathione conjugation of but-3-ene-1,2-diol, 3,4-epoxybutane-1,2-diol, and 1,2;3,4-diepoxybutane. The model reproduced the observed uptake of butadiene and epoxybutene from closed chambers, it simulated tissue epoxide concentrations and depletion of glutathione in liver and lung, and the computed cumulative metabolites reproduced the observed distribution in urine and exhaled breath 42 hr after a 6-hr inhalation exposure to 14C-butadiene. The predicted epoxybutanediol concentration at steady state in liver, lung, and kidney is about double the epoxybutene concentration, consistent with observations of more trihydroxybutyl N7-guanylate adducts than hydroxybutyl adducts in these tissues of butadiene-exposed mice and rats. Dose-response modeling of survival adjusted tumor data demonstrated that the carcinogenic potency of chloroprene in mice is similar to that of 1,3-butadiene.
工作总结:对1,3-丁二烯的两种结构类似物异戊二烯(2-甲基-1,3-丁二烯)和氯丁二烯(2-氯-1,3-丁二烯)的吸入致癌性研究表明了多器官致癌效应,包括1,3-丁二烯致癌性靶点的几个部位。 已经采取了多种研究方法来了解和量化导致这类化学品致癌性的环氧化物形成化学品的影响。对这些化学物质诱导的肿瘤中ras原癌基因遗传改变的分析显示,K-ras密码子61处的A至T颠换占主导地位。为了解释仅经鼻吸入暴露于丁二烯后循环环氧丁烯浓度的过度预测,我们修改了丁二烯处置的早期毒代动力学模型,以描述由于该酶和细胞色素P450之间形成瞬时复合物,内质网结合的环氧化物中间体对环氧化物水解酶(特权进入)的可及性增强。在该模型中,结合的环氧化物P450产物与环氧化物释放到胞质溶胶中竞争水解。该模型扩展到包括水解和/或谷胱甘肽共轭丁-3-烯-1,2-二醇,3,4-环氧丁烷-1,2-二醇和1,2; 3,4-二环氧丁烷。该模型再现了从密闭室中观察到的丁二烯和环氧丁烯的摄取,模拟了组织环氧化物浓度和肝脏和肺中谷胱甘肽的消耗,计算的累积代谢物再现了6小时吸入暴露于14 C-丁二烯后42小时在尿液和呼出气中观察到的分布。在肝脏、肺和肾脏中,预测的稳态环氧丁二醇浓度约为环氧丁烯浓度的两倍,这与在丁二烯暴露小鼠和大鼠的这些组织中观察到的N7-鸟苷酸三羟基丁酯加合物多于羟丁基加合物一致。剂量反应模型的生存调整肿瘤数据表明,氯丁二烯在小鼠中的致癌潜力是类似的1,3-丁二烯。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
RONALD L MELNICK其他文献
RONALD L MELNICK的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('RONALD L MELNICK', 18)}}的其他基金
MECHANISTIC STUDIES ON 1,3-BUTADIENE AND RELATED EPOXIDE-FORMING CHEMICALS
1,3-丁二烯及相关环氧化物形成化学品的机理研究
- 批准号:
6106803 - 财政年份:
- 资助金额:
-- - 项目类别:
TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS
危险物质的毒代动力学和生化模型
- 批准号:
6290095 - 财政年份:
- 资助金额:
-- - 项目类别:
TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS
危险物质的毒代动力学和生化模型
- 批准号:
6106800 - 财政年份:
- 资助金额:
-- - 项目类别:
MECHANISTIC STUDIES ON 1,3-BUTADIENE AND RELATED EPOXIDE-FORMING CHEMICALS
1,3-丁二烯及相关环氧化物形成化学品的机理研究
- 批准号:
6290098 - 财政年份:
- 资助金额:
-- - 项目类别:
TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS
危险物质的毒代动力学和生化模型
- 批准号:
2574468 - 财政年份:
- 资助金额:
-- - 项目类别:
MECHANISM-BASED MODELING OF ALPHA-2U-GLOBULIN ACCUMULATION IN MALE RAT KIDNEY
雄性大鼠肾脏中 ALPHA-2U-球蛋白积累的基于机制的建模
- 批准号:
6106804 - 财政年份:
- 资助金额:
-- - 项目类别:
TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS
危险物质的毒代动力学和生化模型
- 批准号:
6432433 - 财政年份:
- 资助金额:
-- - 项目类别:
MECHANISM-BASED MODELING OF ALPHA-2U-GLOBULIN ACCUMULATION IN MALE RAT KIDNEY
雄性大鼠肾脏中 ALPHA-2U-球蛋白积累的基于机制的建模
- 批准号:
6290099 - 财政年份:
- 资助金额:
-- - 项目类别:
TOXICOKINETIC AND BIOCHEMICAL MODELING OF HAZARDOUOS AGENTS
危险物质的毒代动力学和生化模型
- 批准号:
5202293 - 财政年份:
- 资助金额:
-- - 项目类别:
相似海外基金
Role of prostaglandin terminal synthases in chemical carcinogen-induced carcinogenesis
前列腺素末端合酶在化学致癌物诱发的致癌作用中的作用
- 批准号:
25860100 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Young Scientists (B)
Analysis of microsomal prostaglandin E synthase (mPGES-1) in chemical carcinogen-induced colon carcinogenesis
微粒体前列腺素E合酶(mPGES-1)在化学致癌物诱导结肠癌发生中的分析
- 批准号:
20890220 - 财政年份:2008
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Young Scientists (Start-up)
DNA damage and immunosuppressive cytokines induced by ultraviolet radiation and chemical carcinogen
紫外线和化学致癌物引起的DNA损伤和免疫抑制细胞因子
- 批准号:
14570830 - 财政年份:2002
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
P53, CHEMICAL CARCINOGEN AND ETHANOL IN ORAL CANCER
P53,口腔癌中的化学致癌物和乙醇
- 批准号:
6201791 - 财政年份:1999
- 资助金额:
-- - 项目类别:
MECHANISMS OF CHEMICAL CARCINOGEN INDUCED P53 MUTATIONS
化学致癌物引起P53突变的机制
- 批准号:
6103188 - 财政年份:1998
- 资助金额:
-- - 项目类别:
P53, CHEMICAL CARCINOGEN AND ETHANOL IN ORAL CANCER
P53,口腔癌中的化学致癌物和乙醇
- 批准号:
6104861 - 财政年份:1998
- 资助金额:
-- - 项目类别:
MECHANISMS OF CHEMICAL CARCINOGEN INDUCED P53 MUTATIONS
化学致癌物引起P53突变的机制
- 批准号:
6237666 - 财政年份:1997
- 资助金额:
-- - 项目类别:
P53, CHEMICAL CARCINOGEN AND ETHANOL IN ORAL CANCER
P53,口腔癌中的化学致癌物和乙醇
- 批准号:
6238532 - 财政年份:1997
- 资助金额:
-- - 项目类别: