BIOMAT Database Logo BIOMAT Database Logo

Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity. 2013

Qingsu Xia, and Yuewei Zhao, and Linda S Von Tungeln, and Daniel R Doerge, and Ge Lin, and Lining Cai, and Peter P Fu
National Center for Toxicological Research , Jefferson, Arkansas 72079, United States.

Pyrrolizidine alkaloid-containing plants are the most common poisonous plants affecting livestock, wildlife, and humans. The U.S. National Toxicology Program (NTP) classified riddelliine, a tumorigenic pyrrolizidine alkaloid, as "reasonably anticipated to be a human carcinogen" in the NTP 12th Report on Carcinogens in 2011. We previously determined that four DNA adducts were formed in rats dosed with riddelliine. The structures of the four DNA adducts were elucidated as (i) a pair of epimers of 7-hydroxy-9-(deoxyguanosin-N(2)-yl)dehydrosupinidine adducts (termed as DHP-dG-3 and DHP-dG-4) as the predominant adducts; and (ii) a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N(6)-yl)dehydrosupinidine adducts (termed as DHP-dA-3 and DHP-dA-4 adducts). In this study, we selected a nontumorigenic pyrrolizidine alkaloid, platyphylliine, a pyrrolizidine alkaloid N-oxide, riddelliine N-oxide, and nine tumorigenic pyrrolizidine alkaloids (riddelliine, retrorsine, monocrotaline, lycopsamine, retronecine, lasiocarpine, heliotrine, clivorine, and senkirkine) for study in animals. Seven of the nine tumorigenic pyrrolizidine alkaloids, with the exception of lycopsamine and retronecine, are liver carcinogens. At 8-10 weeks of age, female F344 rats were orally gavaged for 3 consecutive days with 4.5 and 24 μmol/kg body weight test article in 0.5 mL of 10% DMSO in water. Twenty-four hours after the last dose, the rats were sacrificed, livers were removed, and liver DNA was isolated for DNA adduct analysis. DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts were formed in the liver of rats treated with the individual seven hepatocarcinogenic pyrrolizidine alkaloids and riddelliine N-oxide. These DNA adducts were not formed in the liver of rats administered retronecine, the nontumorigenic pyrrolizidine alkaloid, platyphylliine, or vehicle control. These results indicate that this set of DNA adducts, DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, is a common biological biomarker of pyrrolizidine alkaloid-induced liver tumor formation. To date, this is the first finding that a set of exogenous DNA adducts are commonly formed from a series of tumorigenic xenobiotics.

UI MeSH Term Description Entries
D008114 Liver Neoplasms, Experimental Experimentally induced tumors of the LIVER. Hepatoma, Experimental,Hepatoma, Morris,Hepatoma, Novikoff,Experimental Hepatoma,Experimental Hepatomas,Experimental Liver Neoplasms,Hepatomas, Experimental,Neoplasms, Experimental Liver,Experimental Liver Neoplasm,Liver Neoplasm, Experimental,Morris Hepatoma,Novikoff Hepatoma
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D011763 Pyrrolizidine Alkaloids A group of ALKALOIDS, characterized by a nitrogen-containing necine, occurring mainly in plants of the BORAGINACEAE; COMPOSITAE; and LEGUMINOSAE plant families. They can be activated in the liver by hydrolysis of the ester and desaturation of the necine base to reactive electrophilic pyrrolic CYTOTOXINS. Pyrrolizidine Alkaloid,Senecio Alkaloid,Senecio Alkaloids,Alkaloid, Pyrrolizidine,Alkaloid, Senecio,Alkaloids, Pyrrolizidine,Alkaloids, Senecio
D011916 Rats, Inbred F344 An inbred strain of rat that is used for general BIOMEDICAL RESEARCH purposes. Fischer Rats,Rats, Inbred CDF,Rats, Inbred Fischer 344,Rats, F344,Rats, Inbred Fisher 344,CDF Rat, Inbred,CDF Rats, Inbred,F344 Rat,F344 Rat, Inbred,F344 Rats,F344 Rats, Inbred,Inbred CDF Rat,Inbred CDF Rats,Inbred F344 Rat,Inbred F344 Rats,Rat, F344,Rat, Inbred CDF,Rat, Inbred F344,Rats, Fischer
D002273 Carcinogens Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. Carcinogen,Oncogen,Oncogens,Tumor Initiator,Tumor Initiators,Tumor Promoter,Tumor Promoters,Initiator, Tumor,Initiators, Tumor,Promoter, Tumor,Promoters, Tumor
D005260 Female Females
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015197 Carcinogenicity Tests Tests to experimentally measure the tumor-producing/cancer cell-producing potency of an agent by administering the agent (e.g., benzanthracenes) and observing the quantity of tumors or the cell transformation developed over a given period of time. The carcinogenicity value is usually measured as milligrams of agent administered per tumor developed. Though this test differs from the DNA-repair and bacterial microsome MUTAGENICITY TESTS, researchers often attempt to correlate the finding of carcinogenicity values and mutagenicity values. Tumorigenicity Tests,Carcinogen Tests,Carcinogenesis Tests,Carcinogenic Activity Tests,Carcinogenic Potency Tests,Carcinogen Test,Carcinogenesis Test,Carcinogenic Activity Test,Carcinogenic Potency Test,Carcinogenicity Test,Potency Test, Carcinogenic,Potency Tests, Carcinogenic,Test, Carcinogen,Test, Carcinogenesis,Test, Carcinogenic Activity,Test, Carcinogenic Potency,Test, Carcinogenicity,Test, Tumorigenicity,Tests, Carcinogen,Tests, Carcinogenesis,Tests, Carcinogenic Activity,Tests, Carcinogenic Potency,Tests, Carcinogenicity,Tests, Tumorigenicity,Tumorigenicity Test
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D015415 Biomarkers Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, ENVIRONMENTAL EXPOSURE and its effects, disease diagnosis; METABOLIC PROCESSES; SUBSTANCE ABUSE; PREGNANCY; cell line development; EPIDEMIOLOGIC STUDIES; etc. Biochemical Markers,Biological Markers,Biomarker,Clinical Markers,Immunologic Markers,Laboratory Markers,Markers, Biochemical,Markers, Biological,Markers, Clinical,Markers, Immunologic,Markers, Laboratory,Markers, Serum,Markers, Surrogate,Markers, Viral,Serum Markers,Surrogate Markers,Viral Markers,Biochemical Marker,Biologic Marker,Biologic Markers,Clinical Marker,Immune Marker,Immune Markers,Immunologic Marker,Laboratory Marker,Marker, Biochemical,Marker, Biological,Marker, Clinical,Marker, Immunologic,Marker, Laboratory,Marker, Serum,Marker, Surrogate,Serum Marker,Surrogate End Point,Surrogate End Points,Surrogate Endpoint,Surrogate Endpoints,Surrogate Marker,Viral Marker,Biological Marker,End Point, Surrogate,End Points, Surrogate,Endpoint, Surrogate,Endpoints, Surrogate,Marker, Biologic,Marker, Immune,Marker, Viral,Markers, Biologic,Markers, Immune

Related Publications

Qingsu Xia, and Yuewei Zhao, and Linda S Von Tungeln, and Daniel R Doerge, and Ge Lin, and Lining Cai, and Peter P Fu
Pyrrolizidine alkaloid-derived DNA adducts are common toxicological biomarkers of pyrrolizidine alkaloid N-oxides.
October 2017, Journal of food and drug analysis,
Qingsu Xia, and Yuewei Zhao, and Linda S Von Tungeln, and Daniel R Doerge, and Ge Lin, and Lining Cai, and Peter P Fu
Pyrrole-protein adducts - A biomarker of pyrrolizidine alkaloid-induced hepatotoxicity.
July 2018, Journal of food and drug analysis,
Qingsu Xia, and Yuewei Zhao, and Linda S Von Tungeln, and Daniel R Doerge, and Ge Lin, and Lining Cai, and Peter P Fu
Identification of DNA adducts derived from riddelliine, a carcinogenic pyrrolizidine alkaloid.
September 2003, Chemical research in toxicology,
Qingsu Xia, and Yuewei Zhao, and Linda S Von Tungeln, and Daniel R Doerge, and Ge Lin, and Lining Cai, and Peter P Fu
Blood Pyrrole-Protein Adducts--A Biomarker of Pyrrolizidine Alkaloid-Induced Liver Injury in Humans.
January 2015, Journal of environmental science and health. Part C, Environmental carcinogenesis & ecotoxicology reviews,
Qingsu Xia, and Yuewei Zhao, and Linda S Von Tungeln, and Daniel R Doerge, and Ge Lin, and Lining Cai, and Peter P Fu
Clinical application of pyrrole-hemoglobin adducts as a biomarker of pyrrolizidine alkaloid exposure in humans.
February 2021, Archives of toxicology,
Qingsu Xia, and Yuewei Zhao, and Linda S Von Tungeln, and Daniel R Doerge, and Ge Lin, and Lining Cai, and Peter P Fu
Pyrrole-Hemoglobin Adducts, a More Feasible Potential Biomarker of Pyrrolizidine Alkaloid Exposure.
June 2019, Chemical research in toxicology,
Qingsu Xia, and Yuewei Zhao, and Linda S Von Tungeln, and Daniel R Doerge, and Ge Lin, and Lining Cai, and Peter P Fu
Pyrrolizidine Alkaloid-Induced Hepatotoxicity Associated with the Formation of Reactive Metabolite-Derived Pyrrole-Protein Adducts.
October 2021, Toxins,
Qingsu Xia, and Yuewei Zhao, and Linda S Von Tungeln, and Daniel R Doerge, and Ge Lin, and Lining Cai, and Peter P Fu
Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, heliotrine.
May 2008, Toxicology letters,
Qingsu Xia, and Yuewei Zhao, and Linda S Von Tungeln, and Daniel R Doerge, and Ge Lin, and Lining Cai, and Peter P Fu
Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, lasiocarpine.
January 2006, Cancer letters,
Qingsu Xia, and Yuewei Zhao, and Linda S Von Tungeln, and Daniel R Doerge, and Ge Lin, and Lining Cai, and Peter P Fu
Pyrrolizidine alkaloid-induced DNA-protein cross-links.
November 1995, Carcinogenesis,
Copied contents to your clipboard!