DNA adducts of aristolochic acid II: total synthesis and site-specific mutagenesis studies in mammalian cells

Attaluri, Sivaprasad; Bonala, Radha; Yang, In Young; Lukin, Mark; Wen, Yujing; Grollman, Arthur P.; Moriya, Masaaki; Iden, Charles R.; Johnson, Francis

doi:10.1093/nar/gkp815

Cited by 69 publications

(81 citation statements)

References 48 publications

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“…Several recently characterized molecular events, including the intrinsic miscoding properties of dA-AL, in which dAMP is inserted preferentially opposite this lesion during translesion DNA synthesis (27), combine to create the unusual pattern of mutations observed in AA-induced UUC. As with most bulky adducts, dA-AL adducts normally would be excised by global genomic nucleotide excision repair.…”

Section: Discussionmentioning

confidence: 99%

Aristolochic acid-associated urothelial cancer in Taiwan

Chen

Dickman

Moriya³

et al. 2012

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

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Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of 5′ AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.upper urinary tract carcinoma | traditional Chinese medicine | transitional cell carcinoma | DNA damage | herbal medicine

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Section: Discussionmentioning

confidence: 99%

Aristolochic acid-associated urothelial cancer in Taiwan

Chen

Dickman

Moriya³

et al. 2012

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

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391

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“…Site-specific mutagenesis studies in mammalian cells reveal that DNA polymerases frequently incorporate dAMP opposite AL-dA adducts, leading to A-to-T transversions. 43,44 Very recent studies, involving genome-wide sequencing of DNA in tumors of UTUCs from individuals with known exposure to AA, revealed an unusually large number of somatic mutations harboring this uncommon A-to-T transversion attributable to AA. 45,46 Another recent study also reported a high frequency of A–to-T mutations, but also G-to-T transversions as a complementary signature mutation in TP53 of a group of non-smoking women from Belgium who ingested large amounts AA over a short period of time.…”

Section: Metabolic Activation Dna Adduct Formation and Tp53 Mutatiomentioning

confidence: 99%

New approaches for biomonitoring exposure to the human carcinogen aristolochic acid

et al. 2015

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Aristolochic acids (AA) are found in all Aristolochia herbaceous plants, many of which have been used worldwide for medicinal purposes for centuries. AA are causal agents of the chronic kidney disease entity termed aristolochic acid nephropathy (AAN) and potent upper urinary tract carcinogens in humans. AAN and upper urinary tract cancers are endemic in rural areas of Croatia and other Balkan countries where exposure to AA occurs through the ingestion of home-baked bread contaminated with Aristolochia seeds. In Asia, exposure to AA occurs through usage of traditional Chinese medicinal herbs containing Aristolochia. Despite warnings from regulatory agencies, traditional Chinese herbs containing AA continue to be used world-wide. In this review, we highlight novel approaches to quantify exposure to AA, by analysis of aristolactam (AL) DNA adducts, employing ultraperformance liquid chromatography–electrospray ionization/multistage mass spectrometry (UPLC-ESI/MSn). DNA adducts are a measure of internal exposure to AA and serve as an important end point for cross-species extrapolation of toxicity data and human risk assessment. The level of sensitivity of UPLC-ESI/MSn surpasses the limits of detection of AL-DNA adducts obtained by 32P-postlabeling techniques, the most widely employed methods for detecting putative DNA adducts in humans. AL-DNA adducts can be measured by UPLC-ESI/MS3, not only in fresh frozen renal tissue, but also in formalin-fixed, paraffin-embedded (FFPE) samples, an underutilized biospecimen for assessing chemical exposures, and in exfoliated urinary cells, a non-invasive approach. The frequent detection of AL DNA adducts in renal tissues, combined with the characteristic mutational spectrum induced by AA in TP53 and other genes provides compelling data for a role of AA in upper urothelial tract cancer.

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“…To quantify the 32 P-labeled products, integrated values were measured using a ␤-PhosphorImager and compared with the standards. Because ALI-DNA adducts were not available, a known amount (0.0152 pmol) of ALII-dA-or ALII-dG-modified oligodeoxynucleotides was used as a standard (obtained from Francis Johnson, Department of Chemistry, Stony Brook University) (Attaluri et al, 2010).…”

Section: Metabolism Of [ 3 H]aai In Mouse Livermentioning

confidence: 99%

Cytochrome P450 1A2 Detoxicates Aristolochic Acid in the Mouse

Rosenquist¹,

Einolf²,

Dickman³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Aristolochic acids (AAs) are plant-derived nephrotoxins and carcinogens responsible for chronic renal failure and associated urothelial cell cancers in several clinical syndromes known collectively as aristolochic acid nephropathy (AAN). Mice provide a useful model for study of AAN because the renal histopathology of AA-treated mice is strikingly similar to that of humans. AA is also a potent carcinogen in mice with a tissue spectrum somewhat different from that in humans. The toxic dose of AA in mice is higher than that in humans; this difference in susceptibility has been postulated to reflect differing rates of detoxication between the species. Recent studies in mice have shown that the hepatic cytochrome P450 system detoxicates AA, and inducers of the arylhydrocarbon response protect mice from the nephrotoxic effects of AA. The purpose of this study was to determine the role of specific cytochrome P450 (P450) enzymes in AA metabolism in vivo. Of 18 human P450 enzymes we surveyed only two, CYP1A1 and CYP1A2, which were effective in demethylating 8-methoxy-6-nitro-phenanthro- (3,4-d)-1,3-dioxolo-5-carboxylic acid (AAI) to the nontoxic derivative 8-hydroxy-6-nitro-phenanthro-(3,4-d)-1,3-dioxolo-5-carboxylic acid (AAIa). Kinetic analysis revealed similar efficiencies of formation of AAIa by human and rat CYP1A2. We also report here that CYP1A2-deficient mice display increased sensitivity to the nephrotoxic effects of AAI. Furthermore, Cyp1a2 knockout mice accumulate AAI-derived DNA adducts in the kidney at a higher rate than control mice. Differences in bioavailability or hepatic metabolism of AAI, expression of CYP1A2, or efficiency of a competing nitroreduction pathway in vivo may explain the apparent differences between human and rodent sensitivity to AAI.

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DNA adducts of aristolochic acid II: total synthesis and site-specific mutagenesis studies in mammalian cells

Cited by 69 publications

References 48 publications

Aristolochic acid-associated urothelial cancer in Taiwan

Aristolochic acid-associated urothelial cancer in Taiwan

New approaches for biomonitoring exposure to the human carcinogen aristolochic acid

Cytochrome P450 1A2 Detoxicates Aristolochic Acid in the Mouse

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