Full Structure Assignments of Pyrrolizidine Alkaloid DNA Adducts and Mechanism of Tumor Initiation

Zhao, Yarui; Xia, Qingsu; Costa, Gonçalo Gamboa da; Yu, Hongtao; Cai, Lining; Fu, Peter P.

doi:10.1021/tx300292h

Cited by 56 publications

(88 citation statements)

References 34 publications

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“…According to the study of Xia et al (2013), DNA adduct formation is a common biological biomarker of PAinduced tumorigenicity in rats. Previous studies reported that the metabolism of riddelliine by human liver microsomes resulted in a similar metabolic pattern and DNA adduct profile to those formed in the rat liver, suggesting that the mode of action of PAs studied in experimental rodents is highly relevant to humans (Xia et al 2003;Zhao et al 2012). The current PBK model could also translate in vitro concentration-response curves for DNA adduct formation in human liver cells to in vivo dose-response curves for DNA adduct formation in the liver of human.…”

Section: Discussionmentioning

confidence: 80%

Use of an in vitro–in silico testing strategy to predict inter-species and inter-ethnic human differences in liver toxicity of the pyrrolizidine alkaloids lasiocarpine and riddelliine

et al. 2019

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Lasiocarpine and riddelliine are pyrrolizidine alkaloids (PAs) known to cause liver toxicity. The aim of this study was to predict the inter-species and inter-ethnic human differences in acute liver toxicity of lasiocarpine and riddelliine using physiologically based kinetic (PBK) modelling based reverse dosimetry of in vitro toxicity data. The concentration-response curves of in vitro cytotoxicity of lasiocarpine and riddelliine defined in pooled human hepatocytes were translated to in vivo dose-response curves by PBK models developed using kinetic data obtained from incubations with pooled tissue fractions from Chinese and Caucasian individuals, providing PBK models for the average Chinese and average Caucasian, respectively. From the predicted in vivo dose-response curves, the benchmark dose lower and upper confidence limits for 5% effect (BMDL 5 and BMDU 5) were derived and subsequently compared to those previously obtained in rat to evaluate inter-species differences. The inter-species differences amounted to 2.0-fold for lasiocarpine and 8.2-fold for riddelliine with humans being more sensitive than rats. The inter-ethnic human differences varied 2.0-fold for lasiocarpine and 5.0-fold for riddelliine with the average Caucasian being more sensitive than the average Chinese. In conclusion, the present study provides the proof-of-principle to predict inter-species and inter-ethnic differences in in vivo liver toxicity for PAs by an alternative testing strategy integrating in vitro cytotoxicity data with PBK modelling-based reverse dosimetry.

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Section: Discussionmentioning

confidence: 80%

Use of an in vitro–in silico testing strategy to predict inter-species and inter-ethnic human differences in liver toxicity of the pyrrolizidine alkaloids lasiocarpine and riddelliine

et al. 2019

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“…These studies contributed to riddelliine’s classification as a potential human carcinogen [43]. More recently Zhao et al have shown that dehydroriddelliine preferentially binds at the C9 position of DNA forming epimers of 7-hydroxy-9-(deoxyadenosin- N -6-yl) dehydrosupinidine and 7-hydroxy-9-(deoxyguanosin- N -2-yl) dehydrosupinidine and that these adducts are responsible for riddelliine carcinogenesis at a molecular level [44]. It may be riddelliine is unique and produces many more adducts than similar DHPAs.…”

Section: Discussionmentioning

confidence: 99%

Dehydropyrrolizidine Alkaloid Toxicity, Cytotoxicity, and Carcinogenicity

Stegelmeier

Colegate

Brown

2016

Toxins

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Dehydropyrrolizidine alkaloid (DHPA)-producing plants have a worldwide distribution amongst flowering plants and commonly cause poisoning of livestock, wildlife, and humans. Previous work has produced considerable understanding of DHPA metabolism, toxicity, species susceptibility, conditions, and routes of exposure, and pathogenesis of acute poisoning. Intoxication is generally caused by contaminated grains, feed, flour, and breads that result in acute, high-dose, short-duration poisoning. Acute poisoning produces hepatic necrosis that is usually confirmed histologically, epidemiologically, and chemically. Less is known about chronic poisoning that may result when plant populations are sporadic, used as tisanes or herbal preparations, or when DHPAs contaminate milk, honey, pollen, or other animal-derived products. Such subclinical exposures may contribute to the development of chronic disease in humans or may be cumulative and probably slowly progress until liver failure. Recent work using rodent models suggest increased neoplastic incidence even with very low DHPA doses of short durations. These concerns have moved some governments to prohibit or limit human exposure to DHPAs. The purpose of this review is to summarize some recent DHPA research, including in vitro and in vivo DHPA toxicity and carcinogenicity reports, and the implications of these findings with respect to diagnosis and prognosis for human and animal health.

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“…1,30−35 The DNA adducts are a pair of epimers of 7-hydroxy-9-(deoxyguanosin-N 2 -yl) dehydrosupinidine (DHP− dG-3 and DHP−dG-4) and a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N 6 -yl)dehydrosupinidine (DHP−dA-3 and DHP−dA-4). 35 Further studies demonstrated that DHP−dG-3, DHP−dG-4, DHP−dA-3, and DHP−dA-4 were also formed in the liver of rats treated with seven hepatocarcinogenic pyrrolizidine alkaloids and riddelliine N-oxide. 36 These results indicate that this set of DNA adducts is a common biological biomarker of pyrrolizidine alkaloid-induced liver tumor formation.…”

Section: ■ Introductionmentioning

confidence: 99%

Reaction of Dehydropyrrolizidine Alkaloids with Valine and Hemoglobin

Zhao

Wang

Xia

et al. 2014

Chem. Res. Toxicol.

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Pyrrolizidine alkaloid-containing plants are probably the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids exert toxicity through metabolism to dehydropyrrolizidine alkaloids that bind to cellular protein and DNA, leading to hepatotoxicity, genotoxicity, and tumorigenicity. To date, it is not clear how dehydropyrrolizidine alkaloids bind to cellular constituents, including amino acids and proteins, resulting in toxicity. Metabolism of carcinogenic monocrotaline, riddelliine, and heliotrine produces dehydromonocrotaline, dehyroriddelliine, and dehydroheliotrine, respectively, as primary reactive metabolites. In this study, we report that reaction of dehydromonocrotaline with valine generated four highly unstable 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived valine (DHP-valine) adducts. For structural elucidation, DHP-valine adducts were derivatized with phenyl isothiocyanate (PITC) to DHP-valine-PITC products. After HPLC separation, their structures were characterized by mass spectrometry, UV-visible spectrophotometry, (1)H NMR, and (1)H-(1)H COSY NMR spectral analysis. Two DHP-valine-PITC adducts, designated as DHP-valine-PITC-1 and DHP-valine-PITC-3, had the amino group of valine linked to the C7 position of the necine base, and the other two DHP-valine-PITC products, DHP-valine-PITC-2 and DHP-valine-PITC-4, linked to the C9 position of the necine base. DHP-valine-PITC-1 was interconvertible with DHP-valine-PITC-3, and DHP-valine-PITC-2 was interconvertible with DHP-valine-PITC-4. Reaction of dehydroriddelliine and dehydroheliotrine with valine provided similar results. However, reaction of valine and dehydroretronecine (DHR) under similar experimental conditions did not produce DHP-valine adducts. Reaction of dehydromonocrotaline with rat hemoglobin followed by derivatization with PITC also generated the same four DHP-valine-PITC adducts. This represents the first full structural elucidation of protein conjugated pyrrolic adducts formed from reaction of dehydropyrrolizidine alkaloids with an amino acid (valine). In addition, it was found that DHP-valine-2 and DHP-valine-4, with the valine amino group linked at the C7 position of the necine base, can lose the valine moiety to form DHP.

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Full Structure Assignments of Pyrrolizidine Alkaloid DNA Adducts and Mechanism of Tumor Initiation

Cited by 56 publications

References 34 publications

Use of an in vitro–in silico testing strategy to predict inter-species and inter-ethnic human differences in liver toxicity of the pyrrolizidine alkaloids lasiocarpine and riddelliine

Use of an in vitro–in silico testing strategy to predict inter-species and inter-ethnic human differences in liver toxicity of the pyrrolizidine alkaloids lasiocarpine and riddelliine

Dehydropyrrolizidine Alkaloid Toxicity, Cytotoxicity, and Carcinogenicity

Reaction of Dehydropyrrolizidine Alkaloids with Valine and Hemoglobin

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