7-Glutathione-pyrrole and 7-cysteine-pyrrole are potential carcinogenic metabolites of pyrrolizidine alkaloids

References

• Cook JW, Duffy E, Schoental R. Primary liver tumours in rats following feeding with alkaloids of Senecio jacobaea. Br J Cancer. 1950;4:405–410.
   PubMed Web of Science ®Google Scholar
• Edgar JA, Molyneux RJ, Colegate SM. Pyrrolizidine alkaloids: potential role in the etiology of cancers, pulmonary hypertension, congenital anomalies, and liver disease. Chem Res Toxicol. 2015;28:4–20.
   PubMed Web of Science ®Google Scholar
• Fu PP. Pyrrolizidine Alkaloids: Metabolic activation pathways leading to liver tumor initiation. Chem Res Toxicol. 2017;30:81–93.
   PubMed Web of Science ®Google Scholar
• Fu PP, Xia Q, Lin G, Chou MW. Pyrrolizidine alkaloids—genotoxicity, metabolism enzymes, metabolic activation, and mechanisms. Drug Metab Rev. 2004;36:1–55.
   PubMed Web of Science ®Google Scholar
• International Programme on Chemical Safety. Pyrrolizidine alkaloids health and safety guide. Health and Safety Criteria Guide 26; International Programme on Chemical Safety. Geneva, Switzerland: WHO; 1989:19.
   Google Scholar
• Mattocks AR. Chemistry and Toxicology of Pyrrolizidine Alkaloids. London; New York: Academic Press; 1986.
   Google Scholar
• Wiedenfeld H. Toxicity of pyrrolizidine alkaloids—a serious health problem. MÜSBED. 2011;1:79–87.
   Google Scholar
• Schoental R, Head MA, Peacock PR. Senecio alkaloids: Primary liver tumours in rats as a result of treatment with (1) a mixture of alkaloids from S. jacobaea lin.; (2) retrorsine; (3) isatidine. Br J Cancer. 1954;8:458–465.
   PubMed Web of Science ®Google Scholar
• Ruan J, Yang M, Fu P, Ye Y, Lin G. Metabolic activation of pyrrolizidine alkaloids: insights into the structural and enzymatic basis. Chem Res Toxicol. 2014;27:1030–1039.
   PubMed Web of Science ®Google Scholar
• Chou MW, Wang YP, Yan J, Yang Y-C, Beger RD, et al. Riddelliine N-oxide is a phytochemical and mammalian metabolite with genotoxic activity that is comparable to the parent pyrrolizidine alkaloid riddelliine. Toxicol Lett. 2003;145:239–247.
   PubMed Web of Science ®Google Scholar
• Coulombe RA, Jr., Drew GL, Stermitz FR. Pyrrolizidine alkaloids crosslink DNA with actin. Toxicol Appl Pharmacol. 1999;154:198–202.
   PubMed Web of Science ®Google Scholar
• Fu PP, Chou MW, Churchwell M, Wang Y, Zhao Y, et al. High-performance liquid chromatography electrospray ionization tandem mass spectrometry for the detection and quantitation of pyrrolizidine alkaloid-derived DNA adducts in vitro and in vivo. Chem Res Toxicol. 2010;23:637–652.
   PubMed Web of Science ®Google Scholar
• Fu PP, Chou MW, Xia Q, Yang Y-C, Yan J, et al. Genotoxic pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides—mechanisms leading to DNA adduct formation and tumorigenicity. J Environ Sci Health, Part C. 2001;19:353–385.
   Web of Science ®Google Scholar
• Hincks JR, Kim H-Y, Segall HJ, Molyneux RJ, Stermitz FR, Coulombe RA, Jr. DNA cross-linking in mammalian cells by pyrrolizidine alkaloids: structure-activity relationships. Toxicol Appl Pharmacol. 1991;111:90–98.
   PubMed Web of Science ®Google Scholar
• Kim H-Y, Stermitz FR, Coulombe RAJ. Pyrrolizidine alkaloid-induced DNA-protein cross-links. Carcinogenesis. 1995;16:2691–2697.
   PubMed Web of Science ®Google Scholar
• Kim H-Y, Stermitz FR, Li JK-K, Coulombe RAJ. Comparative DNA cross-linking by activated pyrrolizidine alkaloids. Food Chem Toxicol. 1999;37:619–625.
   PubMed Web of Science ®Google Scholar
• Wang YP, Fu PP, Chou MW. Metabolic activation of the tumorigenic pyrrolizidine alkaloid, retrorsine, leading to DNA adduct formation in vivo. Int J Environ Res Public Health. 2005;2:74–79.
   PubMedGoogle Scholar
• Wang YP, Yan J, Beger RD, Fu PP, Chou MW. Metabolic activation of the tumorigenic pyrrolizidine alkaloid, monocrotaline, leading to DNA adduct formation in vivo. Cancer Lett. 2005;226:27–35.
   PubMed Web of Science ®Google Scholar
• Wang YP, Yan J, Fu PP, Chou MW. Human liver microsomal reduction of pyrrolizidine alkaloid N-oxides to form the corresponding carcinogenic parent alkaloid. Toxicol Lett. 2005;155:411–420.
   PubMed Web of Science ®Google Scholar
• Xia Q, Chou MW, Edgar JA, Doerge DR, Fu PP. Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, lasiocarpine. Cancer Lett. 2006;231:138–145.
   PubMed Web of Science ®Google Scholar
• Xia Q, Chou MW, Kadlubar FF, Chan P-C, Fu PP. Human liver microsomal metabolism and DNA adduct formation of the tumorigenic pyrrolizidine alkaloid, riddelliine. Chem Res Toxicol. 2003;16:66–73.
   PubMed Web of Science ®Google Scholar
• Xia Q, Chou MW, Lin G, Fu PP. Metabolic formation of DHP-derived DNA adducts from a representative otonecine type pyrrolizidine alkaloid clivorine and the extract of Ligularia hodgsonnii hook. Chem Res Toxicol. 2004;17:702–708.
   PubMed Web of Science ®Google Scholar
• Xia Q, Ma L, He X, Cai L, Fu PP. 7-Glutathione pyrrole adduct: a potential DNA reactive metabolite of pyrrolizidine alkaloids. Chem Res Toxicol. 2015;28:615–620.
   PubMed Web of Science ®Google Scholar
• Xia Q, Yan J, Chou MW, Fu PP. Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, heliotrine. Toxicol Lett. 2008;178:77–82.
   PubMed Web of Science ®Google Scholar
• Yan CC, Cooper RA, Huxtable RJ. The comparative metabolism of the four pyrrolizidine alkaloids, seneciphylline, retrorsine, monocrotaline, and trichodesmine in the isolated, perfused rat liver. Toxicol Appl Pharmacol. 1995;133:277–284.
   PubMed Web of Science ®Google Scholar
• Yang Y-C, Yan J, Doerge DR, Chan P-C, Fu PP, Chou MW. Metabolic activation of the tumorigenic pyrrolizidine alkaloid, riddelliine, leading to DNA adduct formation in vivo. Chem Res Toxicol. 2001;14:101–109.
   PubMed Web of Science ®Google Scholar
• Zhao Y, Xia Q, Gamboa da Costa G, Yu H, Cai L, Fu PP. Full structure assignments of pyrrolizidine alkaloid DNA adducts and mechanism of tumor initiation. Chem Res Toxicol. 2012;25:1985–1996.
   PubMed Web of Science ®Google Scholar
• Xia Q, Zhao Y, Von Tungeln LS, Doerge DR, Lin G, et al. Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity. Chem Res Toxicol. 2013;26:1384–1396.
   PubMed Web of Science ®Google Scholar
• Yang Y, Yan J, Churchwell M, Beger R, Chan P, et al. Development of a (32)P-postlabeling/HPLC method for detection of dehydroretronecine-derived DNA adducts in vivo and in vitro. Chem Res Toxicol. 2001;14:91–100.
   PubMed Web of Science ®Google Scholar
• Zhu L, Xue J, Xia Q, Fu PP, Lin G. The long persistence of pyrrolizidine alkaloid-derived DNA adducts in vivo: kinetic study following single and multiple exposures in male ICR mice. Arch Toxicol. 2017;91:949–965.
   PubMed Web of Science ®Google Scholar
• Chou MW, Fu PP. Formation of DHP-derived DNA adducts in vivo from dietary supplements and Chinese herbal plant extracts containing carcinogenic pyrrolizidine alkaloids. Toxicol Ind Health. 2006;22:321–327.
   PubMed Web of Science ®Google Scholar
• Yan J, Xia Q, Chou MW, Fu PP. Metabolic activation of retronecine and retronecine N-oxide—formation of DHP-derived DNA adducts. Toxicol Ind Health. 2008;24:181–188.
   PubMed Web of Science ®Google Scholar
• Cooper RA, Huxtable RJ. A simple procedure for determining the aqueous half-lives of pyrrolic metabolites of pyrrolizidine alkaloids. Toxicon. 1996;34:604–607.
   PubMed Web of Science ®Google Scholar
• Chen M, Li L, Zhong D, Shen S, Zheng J, Chen X. 9-Glutathionyl-6, 7-dihydro-1-hydroxymethyl-5 H-pyrrolizine Is the Major Pyrrolic Glutathione Conjugate of Retronecine-Type Pyrrolizidine Alkaloids in Liver Microsomes and in Rats. Chem Res Toxicol. 2016;29:180–189.
   PubMed Web of Science ®Google Scholar
• Lame MW, Morin D, Jones AD, Segall HJ, Wilson DW. Isolation and identification of a pyrrolic glutathione conjugate metabolite of the pyrrolizidine alkaloid monocrotaline. Toxicol Lett. 1990;51:321–329.
   PubMed Web of Science ®Google Scholar
• Lin G, Cui YY, Hawes EM. Microsomal formation of a pyrrolic alcohol glutathione conjugate of clivorine. Firm evidence for the formation of a pyrrolic metabolite of an otonecine-type pyrrolizidine alkaloid. Drug Metab Dispos. 1998;26:181–184.
   PubMed Web of Science ®Google Scholar
• Reed RL, Miranda CL, Kedzierski B, Henderson MC, Buhler DR. Microsomal formation of a pyrrolic alcohol glutathione conjugate of the pyrrolizidine alkaloid senecionine. Xenobiotica. 1992;22:1321–1327.
   PubMed Web of Science ®Google Scholar
• He X, Xia Q, Ma L, Fu PP. 7-Cysteinyl-pyrrole conjugate-a new potential DNA reactive metabolite of pyrrolizidine alkaloids. J Environ Sci Health, Part C. 2016;34:57–76.
   Web of Science ®Google Scholar
• Ma L, Zhao H, Xia Q, Cai L, Fu PP. Synthesis and phototoxicity of isomeric 7, 9-diglutathione pyrrole adducts: Formation of reactive oxygen species and induction of lipid peroxidation. J Food Drug Anal. 2015;23:577–586.
   Web of Science ®Google Scholar
• Churchwell MI, Beland FA, Doerge DR. Quantification of O6-methyl and O6-ethyl deoxyguanosine adducts in C57BL/6N/Tk+/− mice using LC/MS/MS. J Chromat B. 2006;844:60–66.
   PubMed Web of Science ®Google Scholar
• Fu PP, Xia Q, He X, Barel S, Edery N, et al. Detection of pyrrolizidine alkaloid DNA adducts in livers of cattle poisoned with heliotropium europaeum. Chem Res Toxicol. 2017; DOI:10.102/acs.chemrestox.6b00456
   Google Scholar
• Buhler DR, Miranda CL, Kedzierski B, Reed RL. Mechanisms for pyrrolizidine alkaloid activation and detoxification. Adv Exp Med Biol. 1991;283:597–603.
   PubMedGoogle Scholar
• Ji L, Liu T, Chen Y, Wang Z. Protective mechanisms of N-acetyl-cysteine against pyrrolizidine alkaloid clivorine-induced hepatotoxicity. J Cell Biochem. 2009;108:424–432.
   PubMed Web of Science ®Google Scholar
• Neuman MG, Jia AY, Steenkamp V. Senecio latifolius induces in vitro hepatocytotoxicity in a human cell line. Can J Physiol Pharmacol. 2007;85:1063–1075.
   PubMed Web of Science ®Google Scholar
• Yan CC, Huxtable RJ. Effects of monocrotaline, a pyrrolizidine alkaloid, on glutathione metabolism in the rat. Biochem Pharmacol. 1996;51:375–379.
   PubMed Web of Science ®Google Scholar
• Yan CC, Huxtable RJ. The effect of the pyrrolizidine alkaloids, monocrotaline and trichodesmine, on tissue pyrrole binding and glutathione metabolism in the rat. Toxicon. 1995;33:627–634.
   PubMed Web of Science ®Google Scholar