GENETICS OF AFLATOXIN METABOLISM ROLE IN CARCINOGENESIS

黄曲霉毒素代谢在致癌作用中的遗传学

• 批准号: 3166835
• 负责人: HIRA L GURTOO
• 金额: $ 13.79万
• 依托单位: ROSWELL PARK CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-07-01 至 1992-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3166835
• 关键词: aflatoxins; chemical carcinogen; chemical carcinogenesis; circular DNA; cytochrome P450; electron spin resonance spectroscopy; gel electrophoresis; genetic transcription; genetic translation; high performance liquid chromatography; laboratory mouse; laboratory rat; messenger RNA; molecular genetics; nucleic acid sequence; recombinant DNA; toxin metabolism

This proposal represents a continuation of our studies on aflatoxins and cytochromes P-450. The focus of the studies is on the initial steps of aflatoxin B1 (AFB1) carcinogenesis including: (a) activation and deactivation of AFB1 by various cytochromes P-450; (b) elucidation of the genetic regulation of these cytochromes P-450; (c) investigation of the genetic and molecular mechanisms involved in the repression of the cytochromes during multistage hepatocarcinogenesis; and (d) investigation of the molecular and genetic bases of the relationship between cytochromes P-450 repression and induction of hepatocarcinogenesis by AFB1. Various cytochromes P-450 involved in the preferential metabolism of AFB1 via activation and deactivation pathways will be isolated to develop molecular probes (cDNA, genomic DNA). These molecular probes will be characterized and used to elucidate: (a) molecular basis of regioselectivity of various cytochromes P-450 in the metabolism of AFB1 via various pathways; and (b) genetic and molecular alterations required to induce cytochromes P-450 repression during multistage hepatocarcinogenesis. Much of the work will be performed in vivo in rats and in vitro with labeled aflatoxins, bacterial mutagenesis systems, RNA, DNA, and cytochromes P-450 isolated from rats. Particular methods to be used include: radiochemical methods, high pressure liquid chromatography, biochemical and enzymologic methods, ultra-centrifugation, hybridoma and recombinant DNA techniques.

这项建议代表了我们对黄曲霉毒素和 细胞色素P-450。研究的重点是以下几个初步步骤 黄曲霉毒素B1(AFB1)致癌作用包括：(A)激活和 不同细胞色素P-450对黄曲霉毒素B_1的失活作用； 这些细胞色素P-450的遗传调控；(C)对 参与抑制的遗传和分子机制 细胞色素在多阶段肝癌发生中的作用；和(D)研究 细胞色素之间关系的分子和遗传基础 黄曲霉毒素B_1对P-450的抑制和诱导肝癌的发生 多种细胞色素P-450参与黄曲霉毒素B_1的优先代谢 通过激活和失活途径将被隔离以发展 分子探针(cDNA、基因组DNA)。这些分子探测器将是 表征并用于阐明：(A)分子基础 不同细胞色素P-450在黄曲霉毒素B_1代谢中的区域选择性 不同的途径；和(B)基因和分子改变 诱导细胞色素P-450在多阶段肝癌发生过程中的抑制。 大部分工作将在大鼠体内进行，并在体外进行 标记黄曲霉毒素，细菌诱变系统，RNA，DNA和 大鼠细胞色素P-450的分离。须使用的特定方法 包括：放射化学方法、高压液相色谱、 生化和酶学方法，超速离心法，杂交瘤和 重组DNA技术。

项目成果

The effect of inducers of mixed-function oxidases on hepatic microsome-mediated aflatoxin B1 transformation in C3H/10T1/2 cells.

混合功能氧化酶诱导剂对 C3H/10T1/2 细胞中肝微粒体介导的黄曲霉毒素 B1 转化的影响。

• DOI: 10.1016/0041-008x(89)90230-5
• 发表时间: 1989
• 期刊: Toxicology and applied pharmacology
• 影响因子: 3.8
• 作者: Faletto,MB;Gurtoo,HL
• 通讯作者: Gurtoo,HL

Aflatoxin B1-4-hydroxylase is associated with cytochrome P3-450 in C57BL/6 mouse liver.

黄曲霉毒素 B1-4-羟化酶与 C57BL/6 小鼠肝脏中的细胞色素 P3-450 相关。

• DOI: 10.1016/0006-291x(87)91494-x
• 发表时间: 1987
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Koser,PL;Faletto,MB;Bansal,SK;Caballes,L;Bresnick,E;Hines,RN;Gurtoo,HL
• 通讯作者: Gurtoo,HL

Monoclonal antibody phenotyping of interindividual differences in cytochrome P-450-dependent reactions of single and twin human placenta.

单克隆抗体表型分析单个和双胞胎胎盘细胞色素 P-450 依赖性反应的个体差异。

• 发表时间: 1984
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Fujino,T;Gottlieb,K;Manchester,DK;Park,SS;West,D;Gurtoo,HL;Tarone,RE;Gelboin,HV
• 通讯作者: Gelboin,HV

Induction of aryl hydrocarbon hydroxylase and DNA adduct formation in parental and carcinogen transformed C3H/10T1/2 clone 8 cells by benzo[a]pyrene.

苯并[a]芘在亲本和致癌物转化的 C3H/10T1/2 克隆 8 细胞中诱导芳基烃羟化酶和 DNA 加合物形成。

• 发表时间: 1989
• 期刊: Cancer biochemistry biophysics
• 作者: Faletto,MB;Maccubbin,AE;Koser,PL;Vangalio,JA;Gurtoo,HL
• 通讯作者: Gurtoo,HL

Altered expression of cytochrome P450 mRNA during chemical-induced hepatocarcinogenesis and following partial hepatectomy.

在化学诱导的肝癌发生期间和部分肝切除术后细胞色素 P450 mRNA 的表达发生改变。

• DOI: 10.1006/taap.1994.1017
• 发表时间: 1994
• 期刊: Toxicology and applied pharmacology
• 影响因子: 3.8
• 作者: Habib,SL;Srikanth,NS;Scappaticci,FA;Faletto,MB;Maccubbin,A;Farber,E;Ghoshal,AK;Gurtoo,HL
• 通讯作者: Gurtoo,HL