Is aristolochic acid a risk factor for Balkan endemic nephropathy‐associated urothelial cancer?

Arlt, Volker M.; Ferluga, D; Stiborová, Marie; Pfohl‐Leszkowicz, Annie; Vukelić, Mato; Čeović, Stjepan; Schmeiser, Heinz H.; Cosyns, Jean‐Pierre

doi:10.1002/ijc.10602

Cited by 92 publications

(75 citation statements)

References 16 publications

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“…The latter possibility (33) was excluded by the results of a questionnaire administered in 2005 to 1,081 residents of the endemic region as part of an ongoing epidemiologic investigation of EN (unpublished data). A clue that AA poisoning might be involved in the etiology of EN first appeared in reports of renal failure in horses fed hay contaminated with A. clematitis (17,19).…”

Section: Discussionmentioning

confidence: 47%

Aristolochic acid and the etiology of endemic (Balkan) nephropathy

Grollman

Shibutani

Moriya

et al. 2007

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

534

592

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Section: Discussionmentioning

confidence: 47%

Aristolochic acid and the etiology of endemic (Balkan) nephropathy

Grollman

Shibutani

Moriya

et al. 2007

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

534

592

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“…5,6 Specific AA-DNA adducts were also detected in renal specimens of 2 patients suffering from malignant transformation of the urothelium and living in Balkan endemic nephropathy areas. 14 Since the detection and quantitation of specific DNA adducts by the 32 P postlabeling procedure has proven a useful tool to monitor exposure to the plant carcinogen AA in vivo 6,10,11,14 -23 and in vitro, 28 -33 it was utilized in the present study to identify human enzymes involved in AAI activation.…”

Section: Discussionmentioning

confidence: 99%

“…7,8 Recently, a high prevalence of urothelial cancer was found in a large cohort of patients suffering from aristolochic acid nephropathy in Belgium 9,10 and a case with urothelial cancer has also been described in the United Kingdom. 11 It is also noteworthy that AA consumption may be a cause for the development of a similar type of fibrosis of the kidneys with malignant transformation of the urothelium, the Balkan endemic nephropathy, [12][13][14][15] which is widely found in certain areas of Rumania, Croatia, Bosnia, Serbia and Bulgaria along the Danube river basin. [12][13][14][15] This highlights the carcinogenic potential of AA in human beings.…”

mentioning

confidence: 99%

“…11 It is also noteworthy that AA consumption may be a cause for the development of a similar type of fibrosis of the kidneys with malignant transformation of the urothelium, the Balkan endemic nephropathy, [12][13][14][15] which is widely found in certain areas of Rumania, Croatia, Bosnia, Serbia and Bulgaria along the Danube river basin. [12][13][14][15] This highlights the carcinogenic potential of AA in human beings. It is worth noting that herbal remedies containing species of the genus Aristolochia were recently classified as carcinogenic to humans by the International Agency for Research on Cancer.…”

mentioning

confidence: 99%

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Human hepatic and renal microsomes, cytochromes P450 1A1/2, NADPH:Cytochrome P450 reductase and prostaglandin H synthase mediate the formation of aristolochic acid‐DNA adducts found in patients with urothelial cancer

Stiborová

Frei

Hodek

et al. 2004

Intl Journal of Cancer

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135

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Aristolochic acid (AA), a naturally occurring nephrotoxin and carcinogen, has been associated with the development of urothelial cancer in humans. Understanding which human enzymes are involved in AA activation and/or detoxication is important in the assessment of an individual's susceptibility to this plant carcinogen. Using the 32 P postlabeling assay, we examined the ability of microsomal samples from 8 human livers and from 1 human kidney to activate AAI, the major component of the plant extract AA, to metabolites forming adducts in DNA. Microsomes of both organs generated DNA adduct patterns reproducing those found in renal tissues from humans exposed to AA. 7-(deoxyadenosin-N 6 -yl)aristolactam I, 7-(deoxyguanosin-N 2 -yl)aristolactam I and 7-(deoxyadenosin-N 6 -yl)aristolactam II were identified as AA-DNA adducts formed from AAI by all human hepatic and renal microsomes. To define the role of human microsomal enzymes in the activation of AAI, we investigated the modulation of AAI-DNA adduct formation by cofactors and selective inhibitors of microsomal reductases, cytochrome P450 (CYP) enzymes, NADPH:CYP reductase and NADH:cytochrome b 5 reductase. We also determined whether the activities of CYP and NADPH:CYP reductase in different human hepatic microsomal samples correlated with the levels of AAI-DNA adducts formed by the same microsomal samples. On the basis of these studies, we attribute most of the activation of AAI in human hepatic microsomes to CYP1A2. In contrast to human hepatic microsomes, in human renal microsomes NADPH:CYP reductase is more effective in AAI activation. In addition, prostaglandin H synthase is another enzyme activating AAI in renal microsomes. The results demonstrate for the first time the potential of microsomal enzymes in human liver and kidney to activate AAI by nitroreduction.

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“…In a preliminary study of OTA-DNA and AA-DNA adducts in the kidney tissue of three Croatian patients with EN, both types of DNA adducts were found simultaneously in two samples, while no adducts were found in one (38).…”

Section: Ota-dna Aa-dna Adducts and P53 Mutations In En And Aanmentioning

confidence: 44%

Mycotoxic and Aristolochic Acid Theories of the Development of Endemic Nephropathy

Peraica¹,

Domijan²,

Šarić³

2008

Archives of Industrial Hygiene and Toxicology

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Despite many efforts of scientists and epidemiologists, the aetiology of endemic nephropathy (EN) is still unknown. This disease occurs in the rural population of geographically limited areas of Bulgaria, Bosnia and Herzegovina, Croatia, Romania, and Serbia, and a number of theories have been proposed about its aetiology. The mycotoxin theory has prevailed until now, based on the studies of nephrotoxic mycotoxin ochratoxin A (OTA) that revealed higher frequency of OTA-positive food and blood samples in endemic than in non-endemic areas. However, a new aristolochic acid (AA) theory of EN origin has been proposed recently, due to the histological similarities in kidney lesions between patients suffering from EN and patients suffering from Chinese herbs nephropathy caused by AA. Until now it has not been unequivocally proved that the inhabitants of EN areas are exposed to higher concentration of AA than in other regions and the exposure pathways are rather uncertain. This paper presents most important studies supporting both theories, indicating also the inconsistencies of each.

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Is aristolochic acid a risk factor for Balkan endemic nephropathy‐associated urothelial cancer?

Cited by 92 publications

References 16 publications

Aristolochic acid and the etiology of endemic (Balkan) nephropathy

Aristolochic acid and the etiology of endemic (Balkan) nephropathy

Human hepatic and renal microsomes, cytochromes P450 1A1/2, NADPH:Cytochrome P450 reductase and prostaglandin H synthase mediate the formation of aristolochic acid‐DNA adducts found in patients with urothelial cancer

Mycotoxic and Aristolochic Acid Theories of the Development of Endemic Nephropathy

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