DRUG METABOLIZING ENZYMES IN ANIMAL MODELS AND HUMAN TISSUE

动物模型和人体组织中的药物代谢酶

• 批准号: 3918608
• 负责人: J A GOLDSTEIN
• 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/3918608
• 关键词: biological polymorphism; carcinogens; complementary DNA; cytochrome P450; detoxification; drug metabolism; gene expression; genetic library; genetic manipulation; heterozygote; human tissue; immunochemistry; laboratory rat; liver metabolism; liver neoplasms; male; messenger RNA; mutagens; oligonucleotides; oxygenases

The cytochrome P-450 system is the principal monooxygenase system which metabolizes foreign chemicals to both inactive compounds as well as activating them to mutagens and carcinogens. Some of these enzymes are polymorphic in both man and rodents. A polymorphism in a human P-450 (Hp1-1) immunochemically related to rat liver P- 450g has recently been reported. This P-450 appears to be present 1 about 50% of the human population and absent in the remainder. The rat appears to be a good model for the human since rat P-450g is also present in 50% of the population and absent in the remainder. In order to obtain molecular probes to further study this defect in rats and humans, a cDNA library was made from a high 450g rat. Several cDNAs were identified with specific antibody to P-450g. A full-length cDNA for P-450g has been completely sequenced. This cytochrome contains considerable homology to other cytochromes in the P-450IIc subfamily and to the cDNA for the human P-450, Hp1-1. Based on computer analysis, a specific oligonucleotide region of the P-450g cDNA was selected for use in Northerns and Southerns. This oligoprobe confirmed the P-450g in polymorphism rats. However, Northern analysis of RNA from +g and -g rats revealed no difference in mRNA content of +g and -9 phenotypes suggesting that -g rats might contain an alternate, perhaps defective mRNA. Additional studies underway include development in the fetus and neonate and studies to determine whether any extraheptic tissues (more readily studied from humans) contain this RNA. A cDNA library has been constructed from -g male rats, and several putative clones have been selected by hybridization studies. These clones are presently being sequenced to determine whether they are defective, and to develop oligonucleotide probes to allow us to differentiate between +g and -g phenotypes. We are in the process of obtaining human liver samples to investigate the possible role of the human P-450g homolog as a risk factor for liver cancer.

细胞色素P-450系统是主要的单加氧酶系统