Molecular and cellular mechanisms underlying the carcinogenicity and nephrotoxicity of aristolochic acid: hallmarks of a global environmental disease

马兜铃酸致癌性和肾毒性的分子和细胞机制：全球环境疾病的标志

• 批准号: 10005592
• 负责人: Viktoriya S Sidorenko
• 金额: $ 27.91万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005592
• 关键词: Acute; Affinity; Aristolochia; Aristolochic Acids; Asians; Binding; Binding Proteins; Biochemical; Blood; Carcinogens; Cell Death; Cell Fraction; Chemicals; China; Chronic Kidney Failure; Complex; Consumption; Country; DNA; DNA Adducts; Data; Diagnosis; Disease; Drug Kinetics; Early Diagnosis; Epidemiology; Europe; Event; Exposure to; Female; Genes; Genetic; Genomic DNA; Goals; Half-Life; Hepatic Tissue; Herb; Herbal supplement; Human; Incidence; Individual; Ingestion; Injury; Internet; Intrahepatic Cholangiocarcinoma; Kidney; Kidney Diseases; Kinetics; Knowledge; Laboratories; Light; Link; Liver; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Metabolic Pathway; Metabolism; Molecular; Molecular Toxicology; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mouse Strains; Mus; Mutation; Pathway interactions; Plants; Plasma; Predisposition; Prevention; Primary carcinoma of the liver cells; Program Research Project Grants; Property; Proteins; Proteomics; Proximal Kidney Tubules; Public Health; Renal Cell Carcinoma; Renal Tissue; Research; Research Design; Resistance; Risk; Role; Series; Serum Albumin; Slice; Surface Plasmon Resonance; Taiwan; Techniques; Time; Tissues; Toxic effect; Translational Research; Tubular formation; United States; Urinary tract; Urine; Urologic Cancer; Xenobiotics; adduct; analog; cancer diagnosis; carcinogenesis; carcinogenicity; cytotoxicity; design; detoxication; experience; experimental study; genotoxicity; global environment; global health; human tissue; male; mortality; mouse model; nephrotoxicity; novel; organ on a chip; prevent; programs; resistant strain; response; success; sulfotransferase; uptake

Aristolochic acid (AA) is a naturally occurring compound found only in Aristolochia plants. Although Aristolochia species have long been used for medicinal purposes, their carcinogenic and nephrotoxic properties were recognized only recently. Significant amounts of AA are present in herbal supplements marketed through the Internet. And, in China and other Asian countries, where herbal remedies are widely used, 100 million people are estimated to be at risk of developing aristolochic acid nephropathy (AAN), a devastating and uniformly fatal disease. Importantly, AA’s unique mutational signature has clearly demonstrated its worldwide association with upper urothelial tract cancers, bladder cancer, renal cell carcinoma, hepatocellular carcinoma and intrahepatic cholangiocarcinoma. In this research, we use a multipronged approach to solve a complex global health problem. Thus, we propose to identify mechanisms of AA-induced carcinogenicity and nephrotoxicity, important causes of morbidity and mortality worldwide. Our guiding hypothesis is that genes involved in bioactivation and inactivation of AA, and its transport to target tissues, act both independently and together to determine individual susceptibility to AA’s toxic effects. Using an integrated human liver-kidney-on-a-chip, we have recently demonstrated that AA activation occurs primarily in the liver. Activated, chemically labile AA metabolites bind tightly to serum albumin and subsequently are transported to the kidney, where they form covalent adducts with proteins and DNA. In Aim 1, we establish pathways of AA metabolism, monitor the pharmacokinetics of AA, and quantify the distribution of AA metabolites, aristolactam (AL)-DNA adducts, and AL-protein adducts among the blood, urine, and target tissues of sensitive and resistant strains of mice. In Aim 2, we extend our human “organs-on-a-chip” studies and apply mass spectrometric, fluorometric, and plasmon resonance techniques to illuminate the critical role of serum albumin in protecting and transporting activated species of AA. However, although the genotoxic properties of AA account for its carcinogenic effects, the molecular mechanisms of its nephrotoxicity are unknown. We hypothesize that selective binding of AA to proteins in the renal proximal tubule initiates the cytotoxicity underlying AA’s nephrotoxic effects. Thus, in Aim 3, we use novel proteomic techniques, affinity probes, and monoclonal antibodies to explore nephrotoxic events, with the goal of identifying the specific renal tubular proteins involved. Successful completion of this research program will advance significantly our knowledge of mechanisms involved in the dual toxicities of AA. Also, data obtained in this study may provide a basis for establishing individual susceptibility to AA, and will facilitate early diagnosis, prevention, and treatment of AA-induced cancers and chronic renal disease. Given the worldwide exposure to AA, this research has significant implications for global public health. Additionally, the techniques perfected in the three aims of this project will serve as templates for investigating other causes of nephrotoxicity and carcinogenicity.

马兜铃酸（AA）是一种天然存在的化合物，只存在于马兜铃属植物中。虽然马兜铃