Mutagenicity of the two main components of commercially available carcinogenic aristolochic acid in Salmonella typhimurium

Schmeiser, Heinz H.; Pool, B.L.; Wießler, Manfred

doi:10.1016/0304-3835(84)90067-3

Cited by 59 publications

(29 citation statements)

References 8 publications

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“…Several studies have confirmed that the nitro group is important for the mutagenic activity of AA in Salmonella and this mutagenecity was due to enzymic reduction of the NO 2 group to yield the hydroxylamino or even amino analogues [51,52]. Nitroreduction has been reported to be the crucial step in the pathway of metabolic activation of AA to their ultimate mutagenic species and this indicates the importance of nitro group in AA I moiety for its toxic and carcinogenic properties.…”

Section: Discussionmentioning

confidence: 94%

Structure activity relationships of aristolochic acid analogues: Toxicity in cultured renal epithelial cells

Balachandran

Wei

Lin

et al. 2005

Kidney International

160

128

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Section: Discussionmentioning

confidence: 94%

Structure activity relationships of aristolochic acid analogues: Toxicity in cultured renal epithelial cells

Balachandran

Wei

Lin

et al. 2005

Kidney International

160

128

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“…AAs have been employed in a number of in vitro mutagenicity tests. A mixture of AA I and II proved to be mutagenic in the Ames test with S. typhimurium strains (Robisch et al, 1983;Schmeiser et al, 1984). Subsequently, it was established that AA II was more active in S. typhimurium than the acids I and IV (Götzl and Schimmer, 1993;Pistelli et al, 1993).…”

Section: Significant Endogenous Mutagens/carcinogensmentioning

confidence: 95%

“…AAs are direct-acting mutagens in bacteria (Robisch et al, 1983;Schmeiser et al, 1984;Pezzuto et al, 1988). They were activated by bacterial nitroreductases analogous to the activation of other nitro aromatic compounds.…”

Section: Significant Endogenous Mutagens/carcinogensmentioning

confidence: 99%

Molecular Modes of Action of Defensive Secondary Metabolites

Wink

Schimmer

2010

Functions and Biotechnology of Plant Secondary Metabolites

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Secondary metabolites (SM) have been shaped by evolution for more than 500 million years. As a result, many of them have distinctive biochemical and pharmacological properties. The molecular modes of action of the main groups of SM are reviewed in this chapter. Details are given on interactions of SM with proteins that can induce conformational changes and thus a modification of their bioactivity. The fluidity and permeability of biomembranes constitute another important target, which is influenced by many lipophilic and amphiphilic SM. A number of SM can either alkylate or intercalate DNA, which can cause mutations and in consequence cancer or malformations. Many SM are cytotoxic because they interfere with biomembranes, proteins of the cytoskeleton or DNA; they often induce programmed cell death (apoptosis). A large number of SM, especially alkaloids modulate neuronal signal transduction by interfering with ion channels, ion pumps, neuroreceptors, choline esterase, monoamine oxidase and other enzymes related to signal transduction pathways. A typical feature of SM is their ability to modulate more than one molecular target; thus, additive and even synergistic activities can be expected.

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“…AAI and AAII were isolated from the mixture by preparative high-pressure liquid chromatography (HPLC); their purity was 99.7% as estimated by HPLC. 34 All other chemicals were of analytical purity or better. Enzymes and chemicals for the 32 P postlabeling assay were obtained commercially from sources described previously.…”

Section: Chemicalsmentioning

confidence: 99%

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

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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Mutagenicity of the two main components of commercially available carcinogenic aristolochic acid in Salmonella typhimurium

Cited by 59 publications

References 8 publications

Structure activity relationships of aristolochic acid analogues: Toxicity in cultured renal epithelial cells

Structure activity relationships of aristolochic acid analogues: Toxicity in cultured renal epithelial cells

Molecular Modes of Action of Defensive Secondary Metabolites

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

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