QUANTITATIVE DETERMINATION OF ARISTOLOCHIC ACID-DERIVED DNA ADDUCTS IN RATS USING<sup>32</sup>P-POSTLABELING/POLYACRYLAMIDE GEL ELECTROPHORESIS ANALYSIS

Dong, H.; Suzuki, N.; Torres, Maria Cecilia de Araujo Rodrigues; Bonala, Radha; Johnson, Francis; Grollman, Arthur P.; Shibutani, Shinya

doi:10.1124/dmd.105.008706

Cited by 63 publications

(89 citation statements)

References 33 publications

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“…Methods used for the 32 P-postlabeling/ PAGE analysis of AA-derived DNA adducts were described in ref. 29. The mass spectroscopic methods used in this study have been reported (47); experimental details are provided in the legend to Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Toward that end, we used a highly sensitive 32 P-postlabeling/PAGE method (29) to quantify AL-DNA adducts and validated this approach by performing this analysis on renal tissue from a patient with documented exposure to AA. Remarkably, dA-AL adducts were detected 3 years after the patient terminated her exposure.…”

Section: Discussionmentioning

confidence: 99%

“…3B) or in five patients with common forms of chronic renal disease (data not shown). Using 10 g of DNA, the limit of detection in the 32 P-postlabeling/PAGE assay is 3 ϫ 10 9 adducts per dNs (29). DNA from renal cortex of a patient who had not been exposed to Aristolochia.…”

Section: Al-dna Adducts In Renal Tissues Of Patients With Enmentioning

confidence: 99%

“…1). Oligonucleotides containing a single dA-AL-I or dG-AL-I adduct were digested in parallel as controls for the 32 P-postlabeling/PAGE assay (29). The chemical identity of dA-AL-I-and dA-AL-II-DNA adducts in the renal cortex of this patient was established by mass spectrometry (Fig.…”

Section: Identification and Quantitation Of Al-dna Adducts In Human Tmentioning

confidence: 99%

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Aristolochic acid and the etiology of endemic (Balkan) nephropathy

Grollman

Shibutani

Moriya

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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592

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Al-dna Adducts In Renal Tissues Of Patients With Enmentioning

confidence: 99%

Section: Identification and Quantitation Of Al-dna Adducts In Human Tmentioning

confidence: 99%

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Aristolochic acid and the etiology of endemic (Balkan) nephropathy

Grollman

Shibutani

Moriya

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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529

592

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“…However, even though aristolactam I is not a direct DNA binding species, low levels of dA-AAI adduct, with highest levels in one of the target tissues (e.g. renal pelvis) were generated in rats treated with aristolactam I 42 . This is consistent with the formation of dA-AAI adduct by aristolactam I observed after in-vitro activation with different peroxidases such as COX-1 and/or COX-2 that are highly expressed in urothelial tissue 43 .…”

Section: Metabolism Of Aristolochic Acid and Biotransformation Enzymesmentioning

confidence: 99%

The Role of Biotransformation Enzymes in the Development of Renal Injury and Urothelial Cancer Caused by Aristolochic Acid: Urgent Questions and Difficult Answers

Stiborová¹,

Frei²,

Arlt³

et al. 2009

BIOMED PAP

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Background: Ingestion of aristolochic acid (AA) is associated with the development of aristolochic acid nephropathy (AAN), which is characterized by chronic renal failure, tubulointerstitial fibrosis and urothelial cancer. AA may also cause another type of kidney fibrosis with malignant transformation of the urothelium, called Balkan Endemic Nephropathy (BEN). The compound predominantly responsible for the nephropathy and urothelial cancer of AA, is aristolochic acid I (AAI) which is a genotoxic mutagen after metabolic activation The activation pathway involves reduction of the nitro group to a cyclic N-acylnitrenium ion that can form covalent DNA adducts. These specific DNA adducts have been detected in experimental animals exposed to AAI, and in urothelial tissues from AAN patients. In rodent tumours induced by AAI, 7-(deoxyadenosin-N 6 -yl)aristolactam I was the most abundant DNA adduct formed and associated with activation of ras oncogenes through a characteristic transversion mutation. Such A:TT:A mutations have been identified in TP53 of urothelial tumour DNA of an AAN patient and in several patients suffering from BEN along with specific AA-DNA adducts. Understanding which enzymes are involved in AAI activation to species forming DNA adducts and/or detoxification to its O-demethylated metabolite aristolochic acid Ia (AAIa) is important in order to assess susceptibility to this carcinogen.Methods and Results: A literature search. Conclusions:The most important human enzymes activating AAI by simple nitroreduction in vitro are hepatic and renal cytosolic NAD(P)H:quinone oxidoreductase, hepatic microsomal cytochrome P450 (CYP) 1A2 and renal microsomal NADPH:CYP reductase as well as cyclooxygenase which is highly expressed in urothelial tissue. However, the contribution of most of these enzymes to the development of AAN and BEN diseases is still unclear. Hepatic CYP enzymes were found to detoxify AAI to AAIa in mice, and thereby protect the kidney from injury. CYP enzymes of the 1A subfamily seem to play a major role in this process in mouse liver. Likewise, among human CYP enzymes, CYP1A1 and 1A2 were found to be the most efficient enzymes participating in AAI oxidation to AAIa in vitro. Nevertheless, which CYPs are the most important in this process in both animal models and in humans have not been entirely resolved as yet. In addition, the relative contribution of enzymes found to activate AAI to species responsible for induction of urothelial cancer in humans remains still to be resolved.

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Human Biomonitoring of DNA Adducts by Ion Trap Multistage Mass Spectrometry

Guo

Turesky

2016

CP Nucleic Acid Chemistry

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Humans are continuously exposed to hazardous chemicals in the environment. These chemicals or their electrophilic metabolites can form adducts with genomic DNA, which can lead to mutations and the initiation of cancer. The identification of DNA adducts is required for understanding exposure and the etiological role of a genotoxic chemical in cancer risk. The analytical chemist is confronted with a great challenge because the levels of DNA adducts generally occur at less than one adduct per 107 nucleotides, and the amount of tissue available for measurement is limited. Ion trap mass spectrometry has emerged as an important technique to screen for DNA adducts because of the high level sensitivity and selectivity, particularly, when employing multi-stage scanning (MSn). The product ion spectra provide rich structural information and corroborate the adduct identities even at trace levels in human tissues. Ion trap technology represents a significant advance in measuring DNA adducts in humans.

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QUANTITATIVE DETERMINATION OF ARISTOLOCHIC ACID-DERIVED DNA ADDUCTS IN RATS USING³²P-POSTLABELING/POLYACRYLAMIDE GEL ELECTROPHORESIS ANALYSIS

Cited by 63 publications

References 33 publications

Aristolochic acid and the etiology of endemic (Balkan) nephropathy

Aristolochic acid and the etiology of endemic (Balkan) nephropathy

The Role of Biotransformation Enzymes in the Development of Renal Injury and Urothelial Cancer Caused by Aristolochic Acid: Urgent Questions and Difficult Answers

Human Biomonitoring of DNA Adducts by Ion Trap Multistage Mass Spectrometry

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QUANTITATIVE DETERMINATION OF ARISTOLOCHIC ACID-DERIVED DNA ADDUCTS IN RATS USING32P-POSTLABELING/POLYACRYLAMIDE GEL ELECTROPHORESIS ANALYSIS

Cited by 63 publications

References 33 publications

Aristolochic acid and the etiology of endemic (Balkan) nephropathy

Aristolochic acid and the etiology of endemic (Balkan) nephropathy

The Role of Biotransformation Enzymes in the Development of Renal Injury and Urothelial Cancer Caused by Aristolochic Acid: Urgent Questions and Difficult Answers

Human Biomonitoring of DNA Adducts by Ion Trap Multistage Mass Spectrometry

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QUANTITATIVE DETERMINATION OF ARISTOLOCHIC ACID-DERIVED DNA ADDUCTS IN RATS USING³²P-POSTLABELING/POLYACRYLAMIDE GEL ELECTROPHORESIS ANALYSIS