ZIA BC 005708 (ZIA) | |||
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Title | Xenobiotic metabolism, cancer chemoprevention and cancer biomarkers | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Gonzalez, Frank | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $719,839 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2016 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (30.0%) Cancer (100.0%) Digestive Diseases (60.0%) |
Colon/Rectum (20.0%) Liver Cancer (40.0%) |
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Research Type | |||
Normal Functioning Exogenous Factors in the Origin and Cause of Cancer |
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Abstract | |||
Irinotecan, also called CPT-11, is a topoisomerase 1 inhibitor used for the treatment of colon cancer. However, CPT-11 treatment leads to adverse effects, including leukopenia, diarrhea, and mucositis. The mechanisms for these toxic responses were investigated, revealing a significant contribution of the intestinal drug-metabolizing enzyme UDP-glucuronosyltransferase (UGT) 1A1 towards CPT-11-induced intestinal damage. Interleukin-33 (IL-33) was also demonstrated to mediate CPT-11-induced intestinal mucositis and severe diarrhea, and inhibition of the IL-33/ST2 pathway could limit mucositis. Targeted inhibition of interleukin-18 (IL-18) can attenuate CPT-11-induced intestinal mucositis in mice. However, the mechanism by which these cytokines are altered remains to be defined. Metabolomics is an important tool in determining the compositions and levels of metabolites in a serum, urine, cells, and tissues. Through analyzing the biological function of altered metabolites, clues to the mechanisms of toxicity can sometimes identified. For example, an important role of lipid metabolism in trichloroethylene-induced liver toxicity was revealed using metabolomics. Gemfibrozil-induced disruption of lysophosphatidylcholine and bile acid homeostasis was found to be a key factor in gemfibrozil-induced hepatotoxicity. The present study aimed to investigate the mechanism of CPT-11-induced metabolic disorders by analysis of endogenous metabolites using metabolomics. Furthermore, the function of metabolites altered by CPT-11-induced toxicity was explored. Irinotecan (CPT-11) is a first-line anti-colon cancer drug, however; CPT-11-induced toxicity remains a key factor limiting its clinical application. To search for clues to the mechanism of CPT-11-induced toxicity, metabolomics was applied using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Intraperitoneal injection of 50 mg/kg of CPT-11 induced loss of body weight, and intestine toxicity. Changes in gallbladder morphology suggested alterations in bile acid metabolism, as revealed at the molecular level by analysis of the liver, bile, and ileum metabolomes between the vehicle-treated control group and the CPT-11-treated group. Analysis of immune cell populations further showed that CPT-11 treatment significantly decreased the IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes, but not in spleen or mesenteric lymph nodes. In vitro cell culture studies showed that the addition of bile acids deoxycholic acid and taurodeoxycholic acid accelerated the CPT-11-induced suppression of IL-10 secretion by activated CD4+ naive T cells isolated from mouse splenocytes. These results showed that CPT-11 treatment caused metabolic changes in the composition of bile acids that altered CPT-11-induced suppression of IL-10 expression. Perfluorodecanoic acid (PFDA) is widely used in production of many daily necessities based on their surface properties and stability. It was assigned as a Persistent Organic Pollutant in 2009 and became a public concern partly because of its potential for activation of the peroxisome proliferator-activated receptor alpha (PPARalpha). In this study, wild-type and Ppara-null mice were administered PFDA. Blood and liver tissues were collected and subjected to systemic toxicological and mechanistic analysis. UPLC-ESI-QTOFMS-based metabolomics was used to explore the contributing components of the serum metabolome that led to variation between wild-type and PPARalpha-null mice. Bile acid homeostasis was disrupted, and slight hepatocyte injury in wild-type mice accompanied by adaptive regulation of bile acid synthesis and transport was observed. The serum metabolome in wild-type clustered differently from that in PPARalpha-null, featured by sharp increases in bile acid components. Differential toxicokinetic tendency was supported by regulation of UDP-glucuronosyltransferases dependent on P |